Exam 3 Flashcards
1
Q
Cancer is:
A
• a disease of uncontrolled cell proliferation
• the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes
• cell growth becomes uncoupled from the hormonal and metabolic conditions that normally maintain homeostasis
2
Q
Colorectal cancer gene alterations
A
(normal epithelium) Loss of APC—> (hyper proliferative epithelium, early adenoma) activation of Ras—> (intermediate adenoma) loss of tumor suppressor gene—> (late adenoma) loss of p53 activity—> (carcinoma) additional alterations—> metastases
3
Q
Which cancers have the fewest mutations, and are driven by only single changes typically?
A
• blood cancers
• pediatric cancers
4
Q
Causes of DNA mutations:
A
• DNA replication errors, chromosome segregation errors
• chemical damage to DNA
• oxidative stress, pathological and physiological
• radiation
• virus infection
• infidelity in DNA repair
5
Q
Proto-oncogenes normally function to:
A
Promote cell proliferation, and physiologically there expression an activity are tightly regulated
6
Q
What are the types of mutations that convert proto-oncogenes to oncogenes?
A
• point mutation
• gene rearrangement
• gene amplification
7
Q
Single base changes within a coding sequence leading to overactive enzymes, or enzymes with different substrates/products
A
- Phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) activating mutations in breast cancer
- Isocitrate dehydrogenase (IDH2) mutations in glioblastoma
8
Q
Example of mutations in promoters that cause hyperactive expression of genes
A
• telomerase (TERT) promoter activating mutations in urothelial cancer
9
Q
The fusion of chromosomes 9 and 22
A
• chronic myelogenous leukemia
• Proto oncogene becoming activated through rearrangements of short DNA fragments or large pieces of chromosomes— more common in blood cancer
10
Q
What gene is amplified in human breast cancer?
A
• Cyclin D1
• increases their copy number and expression amount
11
Q
Tumor suppressor gene RB1
A
• retinoblastoma protein (Rb) encoded tumor suppressor gene
• it’s normal function is to bind and inactivate E2F transcription factors
• when myogenic signal increases cyclin D1, Rb is phosphorylated, and that releases E2F causing increased transcription of genes that promote DNA replication
12
Q
For a tumor suppressor to become inactivated:
A
Both alleles must be lost
13
Q
What is the most frequently mutated tumor suppressor in human cancers?
A
p53 encoded by TP53 gene
• it’s normal function is to respond to DNA damage by halting the replication fork, initiating DNA repair, arresting the cell cycle at G1-S checkpoint, and increasing apoptosis
14
Q
Log kill model
A
• assumes that cancer cells have the same rate in proliferation at all stages of disease
• example: if a given drug can reduce cancer burden from 10^10 to 10^7, I can also reduce the cancer burden from 10^18 to 10^15, and so on
15
Q
What does debulking the tumor do?
A
This is a surgical procedure before chemotherapy in order to lower the tumor burden and decrease the number of chemotherapy cycles required
16
Q
Gompertzian growth model
A
• human tumors follow this rather than a logarithmic growth
• early stages of tumorigenesis: Cancer cell proliferation is limited by the ability of the vasculature and supply of oxygen/nutrients
• later stage of tumorigenesis: Cancer cell proliferation is limited by the accumulation of lethal mutations
• the cell cycle is most active right in the middle, during the angiogenic switch
17
Q
G1 phase:
A
• a checkpoint, in which signals from the extracellular environment, are integrated into a decision whether to proliferate or not (40% of time)
18
Q
S phase
A
• when genomic DNA is duplicated (DNA synthesis) (39% of time)
19
Q
G2 phase
A
• a checkpoint in which the integrity of DNA replication is assessed
• synthesis of cellular components for mitosis (19% of time)
20
Q
M phase
A
• mitosis, in which replicated, chromosomes, segregate, and the cell divides into two daughter cells (2% of time)
21
Q
G0 phase
A
• Quiescent, or non-replicative state
• metabolism still occurs, but replication and division is not active
22
Q
Cell cycle specific drugs
A
• cytotoxic chemotherapy drugs. Their target only exists for a discreet period In the cell cycle.
• Taxane/paclitaxel
• 5-fluorouracil
23
Q
Taxane/paclitaxel
A
Cell cycle specific drug that stabilizes mitotic spindles in the M phase, preventing division into two daughter cells
24
Q
5-fluorouracil
A
Cell cycle specific chemotherapy that inhibits thymidine synthase, an enzyme expressed during S phase
25
Which part of the cell cycle do alkylating agents work?
G1
26
Which part of the cell cycle do vinca alkaloids work?
M phase, G1
27
Which part of the cell cycle do taxoids work?
G2-M
28
Which part of the cell cycle do Anti-metabolites work?
S phase
29
Which part of the cell cycle do antitumor antibiotics work?
G1, S phase
30
Cell cycle nonspecific drugs
• the targets of these drugs, exist throughout the cell cycle and in G0.
• their toxicity may be manifested as cells progress through a specific phase
• anthracycline doxorubicin
• platinum analog cisplatin
31
Anthracycline doxorubicin
• a cell cycle nonspecific chemotherapy drug that intercalates double stranded DNA throughout the cell cycle. This causes double stranded DNA breaks and cell death, mainly in S phase
32
Platinum analog cisplatin
• a cell cycle non-specific chemotherapy drug that causes intrastrand cross-links in DNA throughout the cell cycle. This causes DNA breaks and cell death, mainly in S phase
33
What is a common strategy for sequencing, chemotherapy agents?
1. Cell cycle non-specific drug first.
2. Cell cycle specific drug second
• the CCNS reduces tumor burden into a phase of high cell cycle turnover— this is where the CCS will work better
34
Traditional view of cancer pharmacology
The dominant feature of cancer is uncontrolled cell proliferation, and cancer cells are the most rapidly dividing cells in the body. Using agents that kill cells as they progress through the cell cycle, we can adjust the dosing so that cancer cells are killed while sparing healthy tissues that are not rapidly dividing.
35
Problems with the traditional view of cancer pharmacology
1. There are some tissues that divide rapidly (hematopoietic, GI)
2. Some cancer cells can survive in a quiescent or nondividing state, and therefore will not be affected by the drug
36
Emerging view of cancer pharmacology
Proliferation in cancer cells is driven by a Hallmark phenotype/phenotypes. By targeting the drivers of cell proliferation in cancer cells, off target affects will be minimized.
Problems: we do not know the drivers of all cancers, target agents do have off target effects still, and target agents are very expensive
37
Hallmarks of cancer 2000-2022
• Description of general features that were required for cancer progression. This paper was used to find vulnerabilities that could be therapeutically exploited to improve Cancer care.
• divisions:
1. Resisting cell death.
2. Inducing angiogenesis.
3. Sustaining proliferative signaling
4. Enabling replicative immortality.
5. Activating invasion and metastasis.
6. Evading growth suppressors
38
Antigen processing is:
- the conversion of native proteins into Major Histocompatibility Complex (MHC)-associated peptides
39
Antigen presentation is:
- the display of self and foregin peptides by the MHC on antigen presenting cells (APCs- dendritic cells, macrophages, B cells, vascular endothelial cells, and thymic epithelial cells) to T cells
40
What are the common routes of antigen entry?
1. Antigens from epithelial and connective tissues collected in lymph node
2. Blood-borne antigens collected in the spleen
41
What is a part of T cell recognition of Peptide:MHC complexes?
- T cell contact residue of antigen peptide
- Polymorphic residue of MHC
- Anchor residue of peptide in MHC complex
- Peptide
- T cell receptor
- MHC complex
42
Dendritic cells and antigen presenting
- constitutive expression of MHC class 2
- increased with maturation, and increased by IFN-gamma, and T cell CD40L:CD40 interaction
- constitutive co-stimulator activation, increased with TLR singaling, IFN-gamma, and CD40L:CD40 interaction,
- principle function: antigen presentation to naive T cells
43
Macrophages and antigen presenting
- Low/negative expression of MHC class 2
- increased by IFN-gamma, cells CD40L:40 interaction
- expression of co-stimulators is increased w/TLR signaling, IFN-gamma, and T cell CD40L:40
- principle function: antigen presentation to effector CD4+ T cells in effector phase of cell-mediated killing of microbes (CD8+)
44
B cells and antigen presenting
- Expression of MHC class 2 is constitutively active, increased by IL4, antigen receptor cross-linking, and T cell CD40L:CD40 interaction
- co-stimulator expression is increased by CD40L:CD40 interaction and antigen receptor cross linking
- principle function: antigen presentation to effector CD4+ cells in humoral immune response (T helper-B cell interactions)
45
Vascular endothelial cell and antigen presentation
- Expression of MHC class 2 is increased by IFN-gamma, and constitutive in some blood vessels
- Co-stimulators are low, possibly inducible
- principle function: may promote activation of antigen specific T ells at antigen exposure site and in organ grafts
46
Thymic endothelial cells and antigen presentation
- Expression of MHC class 2 is constitutive
- There are no known co stimulators
- Principle function: positive and negative selection of developing T cells
47
Langerhans cells
tissue-resident dendritic cells in epidermis
48
Trogocytosis
The transfer of functional membrane fragments and their associated molecules directly from one cell to another cell -- macrophages sample the antigen and keep it on the outside of their membranes (not intracellular)
49
Cytosolic pathogens
- degraded in the cytosol
- peptides bind to MHC class 1
- presented to effector CD8 T cells
- effect on presenting cell: death
50
Intravesicular pathogens
- degraded in endocytic vesicle (low pH)
- peptides bind to MHC class 2
- presented to effector CD4 T cells
- effect on presenting cell: activation of macrophage to kill intravesicular bacteria and parasites
51
Extracellular pathogens and toxins
- degraded in endocytic vesicles (low pH)
- peptides bind to MHC class 2
- presented to effector CD4 T cells
- effect on presenting cells: activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins/viruses
52
MHC Class 1 (self/non-self)
- expressed on ALL nucleated cells of the body
- Bind and present ENDOGENOUS (within the cell) antigens
- Cytosolic pathway: intracellular protein synthesis of endogenous proteins
- proteasome (required)
- 8-10 amino acids
- presents to CD8 T cells --> cell lysis
53
MHC class 2
- expressed on antigen presenting cells (APCs)
- Bind and present EXOGENOUS (ingested) antigens
- Endocytic pathway: endocytic uptake of exogenous proteins
- Endolysosome
- 13-18 amino acids
- Present to CD4 T cells --> B cell response --> antibodies (plasma cell creation)
54
Cross presentation
Process by which anitgens of other cells (ex. virally infected or tumor cells) are presented by dendritic cells. These extracellular antigens are taken up by dendritic cells (phagocytosis), processed, and presented by MHC class 1
55
Beta-2 microglobulin
Soluble subunit on all MHC Class 1 cells
56
TAP
transports peptides from cytosol to ER Lumen
57
Calnexin
assists in folding of heavy chain of MHC class 1. Stabilizing MHC class 1 and preventing aggregation (aggregation would cause conformational change, and binding could not occur)
58
ERp57
catalyzes formation of disulfide bonds
59
Calreticulin
replaces calnexin and binds ERp57
60
Tapasin
Binds to ERp57 and Calreticulin, stabilizing the peptide loading complex. Acts as a bridge between MHC class 1 and TAP to keep MHC class 1 close to incoming peptides. Stabilized TAP, increasing flow of peptides into ER lumen.
61
Peptide loading complex
facilitates translocation and loading of peptides onto MHC class 1. Compromised of MHC class 1, TAP, ERp57, Tapasin, and calreticulin
62
MHC 2 antigen processing and presentation:
Synthesis of class 2 MHC in ER --> transport of class 2 MHC and Ii to vesicle --> binding of processed peptides to class 2 MHC --> transport of peptide:MHC2 complex to cell surface --> expression of peptide:MHC complex on cell surface
63
MHC 1 antigen processing and presentation:
Production of proteins in or delivery to the cytosol --> proteolytic degradation of proteins --> peptide transport from cytosol to ER --> assembly of peptide:MHC1 complexes in ER --> surface expression of peptide:MHC1 complexes
64
Invariant chain (Ii)
associated with newly synthesized MHC class 2. Facilitates transport of MHC class 2 to the endolysosome
65
Class 2-associated Ii chain polypeptide (CLIP)
proteasome-cleaved remnant of the Ii chain occupying the peptide binding groove of MHC class 2 until removed by HLA-DM
66
HLA-DM
Catalyzes removal of CLIP and the loading of antigenic peptides into the peptide binding groove on MHC class 2
67
Innate and adaptive working together:
Production of IFN-gamma --> cytokine-mediated MHC2 expression on APCs --> enhanced antigen presentation --> enhanced T cell response
68
Development of T cells
Multipotent HSC --> common lymphoid progenitor --> T cell, ILC precursor--NOTCH/GATA3--> Pro-T cell --> alpha/beta or gamma/delta T cells
69
Thymic involution
- thymic production is greatest before puberty
- as we age, hematopoietic stem cells reduce lymphoid and increase myeloid differentiation capacity
- thymic involution is the loss of thymic mass with age
70
Double negative
Cells that do not express CD4 or CD8. These cells are the first before CD3 takes place
71
Double positive
Cells that express both CD4 and CD8. Prospective alpha-beta T cells proceed through development this way
72
c-kit (CD117)
expressed early in T cell development, aids in early lymphocyte development
73
What is the role of CD44?
Homing precursor cells to the thymus
74
Stages of Double negative T cells in the Thymic cortex
1. ETP (DN1): C-kit ++, Cd44 +, CD25 -
2. Pro-T (DN2): C-kit ++, CD44 +, CD25 +
3. Small pre-T (DN3): C-kit +, CD44 -, CD25 +, pre-TCR bound
4. Large pre-T (DN4): C-kit low/-, Cd44 -, Cd25 -, proliferation occurs here
75
Stages of double positive T cells
- before this occurs, the TCR-alpha locus rearrangement occurs to have double +
1. Cortex: CD4 and CD8
2. Medulla: CD4 and CD8 and TCR
3. progresses to single positive (Cd4 or CD8) with TCR
76
Gene rearrangement with alpha-beta T cells
- V gene rearranges with DJ
- rearranged beta chain associates with surrogate alpha chain to form complex CD3 (forming pre-TCR)
- beta rearrangement stops, initiates proliferation
- now double + thymocyte and alpha chain undergo rearrangements followed by positive and negative selection
77
Positive selection
- only T cell receptors that bind with sufficient strength (low avidity) to self peptide presented by MHC on thymic epithelium receive survival signals. Other cells die due to neglect (no TCR signals) via apoptosis
- this process determines if surviving thymocyte becomes CD4 or Cd8
78
Negative selection
- Thymocytes that react strongly (high avidity) to antigens presented by self-MHC are deleted (prevents autoreactivity)
- AIRE
79
What is responsible for non-thymic peptide presentation to developing T cells?
Autoimmune regulator (AIRE) that express antigen from all over the body
80
NOTCH signaling is required for what?
Initial signaling instruction and guidance through the cortex
81
Chemokines regulate thymocytes migration through various regions of the thymus via:
- initially through CXCR4 and CCR7
- further outward migration via CCR9
- single positive thymocytes gain expression of CCR7 and return to medulla (AIRE and central tolerance)
82
T cell activation requires:
2 SIGNALS:
1. MHC antigen presentation
2. co-receptor signal
signal 3: supports T cell differentiation. cytokines support further subset differentiation
- without these two signals the T cell becomes anergic
83
Examples of co-receptor signaling:
CD40:CD40L
PD-1L:PD-1
ICOS-L:ICOS
CD80/86:CD28 CS80/86:CTLA4
84
T helper differentiation (polarization)
following interaction with their cognate antigen, naive Cd4 T cells are driven by cytokines in the micro-environment and transcription factors to further develop into specific CD4 T helper subsets
85
Promoter of differentiation: IFN-gamma
- Cell: Th1
- transcription factor: Tbet
- signature cytokines: IFN-gamma
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: intracellular pathogens (viral, bacterial)
86
Promoter of differentiation: IL-4
- Cell: Th2
- transcription factor: GATA3
- signature cytokines: IL4, 5, 13, 9
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: allergies, helminth infections
87
Promoter of differentiation: IL-21
- Cell: Th17
- transcription factor: RORyt
- signature cytokines: IL17, IL22
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: extracellular bacterial infections, celiac, auto-immune (IL17)
88
Promoter of differentiation: TGF-beta
- Cell: Treg
- transcription factor: Foxp3
- signature cytokines: TGF-beta
- stability of phenotype: yes
- cytotoxic potential: yes
- disease involvement: immune suppression, homeostasis, tolerance
89
Promoter of differentiation: IL-21
- Cell: Tfh (follicular helper, secondary lymphoid ONLY)
- transcription factor: Bcl-6
- signature cytokines: IL-21
- stability of phenotype: yes
- cytotoxic potential: ND
- disease involvement: B cell maturation in germinal center
90
Superantigen
- recognized by T cells without being processed into peptides presented by MHC molecules
- bind independently to MHC class 2 and the T cell receptor (to coreceptor area)
- does NOT prime pathogen-specific adaptive immune response
- massive cytokine production by CD4 T cells that result in system toxicity, and suppression of adaptive immune system
91
Common bacterial superantigens
1. staphylococcal enterotoxins (SEs)
2. toxic shock syndrome toxin-1 (TSST-1)
92
What are the chain types in T cells receptors?
- alpha-beta
- delta-gamma
- each has a constant and a variable portion
- V(D)J, takes place in the thymus
- both alpha and beta have transmembrane domains
93
alpha chain of T cell receptors
- encoded by VJ and Constant gene segments
- rearrangement --> VJ combo + single C segment
- alpha chain has a transmembrane cytoplasmic tail making the TCR alpha receptor a membrane bound chain
94
beta chain of T cell receptors
- encoded by VDJ and constant gene segments
- rearrangement --> VDJ combo + one of 2 constant gene segments
- beta chain has a transmembrane cytoplasmic tail making the TCR alpha receptor a membrane bound chain
95
Pre-T cells express:
RAG1 and RAG2: to recognize conserved recombination signal sequences flanking the regions of the V, D, and J coding sequences in the DNA
TdT: somatic mutation to add/deletion 0-6 nucleotide bases between the V and D and between the D and J
96
What can B cell recombination do that T cell cannot?
Somatic HYPERMUTATION-- could leading to autoimmunity
97
CD4 co-receptors
- 55kDa monomer with four Ig-like domains (larger)
- binds to conserved regions on class 2 MHC
- binds to signal transduction molecule p56Ick and forms a bridge that also binds to the zeta chains of CD3 (activation or effector functions)
98
CD8 co-receptor
- 30-38 kDa monomers with one Ig-like domain held together by a disulfide bond
- alpha-beta heterodimer or alpha-alpha homodimer
- binds to a conserved region on the Class 1 MHC
99
Principle of T cells: recognition of self
- T cells do not "see" antigen alone, but only antigen presented to them on the surface of a genetically-identical cell (must recognize self)
- APCs must come from individuals who have the same alleles at the MHC loci group
- T cells are antigen-specific and MHC-restricted
100
When antigen is endocytosed and presented by a dendritic cell:
- associates with Class 2 MHC molecules in the endocytosed vesicle
- Th1, Th17, Tfh, Treg, Th2 are programmed to recognized peptides on class 2 molecules
101
Proteins are synthesized within the cell itself:
- class 1 MHC
- NOT taken up by endocytosis
- normal self proteins --> mutations
- internal pathogens such as virus-encoded molecules
- CTL are programmed to see antigen in association with MHC class 1 molecules
102
Why is the dendritic cell special?
- It allows some peptides from antigens it has eaten to leak over into its endogenous pathway, so that it can present them on Class 1 AND Class 2 MHC at the same time: CROSS PRESENTATION
103
How many different MHC1/MHC2 variants can you have?
1. Class 1 MHC molecules = 6 different complexes
2. Class 2 MHC molecules = 12 different complexes
104
What MHC proteins are considered MHC3?
- complement proteins
- TNF-alpha and TNF-beta
105
MHC1 subclasses
- HLA-A
- HLA-B
-HLA-C
- all of these associate with beta-2 microglobulin
- inherited via mom and dad which pair with eachother (2 combos x 3 variations)
106
MHC2 subclasses
- HLA- DP
-HLA- DQ
- HLA-DR
- alpha and beta chains must be paired with same flavor (DR alpha with DR beta, etc.)
- inherited via mom and dad, which can pair with eachother or themselves (4 combos x 3 variations)
107
Each locus of Class 1 and 2 MHC is polymorphic giving us:
- unique identity, permitting the recognition of self versus non-self and is an impediment to organ transplantation
- affects ability to make immune response
- affects the resistance/susceptibility to infectious diseases
- affects the susceptibility to autoimmune diseases and allergies
* most polymorphisms are in the cleft region (antigenic binding site)
108
Cytosolic pathway
- presentation of antigen on Class 1 molecules
- requires intracellular protein synthesis of the endogenous antigen
109
What are defective ribosomal products (DRiPs)?
- proteins that are synthesized incorrectly.
- associated with MHC 1 class
- allows recognition and killing of cells that have aberrant DNA and thus produce aberrant proteins
110
What do virus-infected cells contain that is distinct?
- 20S proteasome
- induced by IFN-gamma and TNF-alpha
- proteasome degrades and presents viral proteins on the cell surface through MHC class 1 molecules
- allows for the recognition and killing of cells that are infected with viruses
111
Endocytic pathway
- presentation of antigen on MHC class 2 molecules
- requires the endocytic uptake of exogenous antigen
112
Endocytic degradation pathway
- exogenous antigens are processed through the endocytic pathway
- antigens are internalized into APCs through endocytosis or phagocytosis (dendritic/macrophages phagocytose, B cells endocytose)
- internalized antigens are degraded in phagolysosomes or endosomes
- the antigenic peptides are associated with MHC class 2 molecules on their cell surface
113
invariant chain
- MHC class 2 molecules are synthesized on the RER as trimers
- alpha and beta chain coupled with an invariant chain (CD74)
- the invariant chain assists in the folding of the class 2 alpha and beta chains, binds to the peptide-presenting site of the class 2 molecule, and assists in the transport of the MHC class 2 molecules from the golgi to the cytoplasmic vesicles
114
What gradually digests the invariant chain leaving a short fragment (CLIP) bound to the antigen presenting site of the MHC class 2?
Proteolytic cleavage
115
CLIP
Class 2-associated invariant chain peptide
116
assembly of class 2 MHC molecules
- a nonclassical class 2 MHC is required to catalyze the exchange of antigenic peptide for the CLIP-- AKA, HLA-DM (which is regulated by HLA-DO)
117
HLA-B27 polymorphism
- individuals are 90x more likely to develop ankylosing spondylitis (destruction of the vertebral cartilage)
- also linked to psoriasis, IBS, and Reiter's syndrome
118
HLA-B57 polymorphism
- linked to Abacavir hypersensitivity
119
HLA-DR2 polymorphism
- individuals are 130x more likely to develop narcolepsy
120
HLA-A3 and HLA-B14 polymorphism
- individuals are 90x more likely to develop hemochromatosis (too much iron absorption which can lead to internal organ damage)
121
HLA-DQ2 and HLA-DQ8 polymorphism
- linked to Celiac disease
122
HLA-DR3 polymorphism
- linked to diabetes mellitus type I, Grave's disease, Addison disease, and Hashimoto thyroiditis
123
HLA-DR4 polymorphism
- linked to Rheumatoid arthritis, diabetes mellitus type 1, and Addison disease
124
HLA- B53 polymorphism
- associated with protection against childhood malaria
- specific global distribution pattern (Ghana frequency is 40% while China and South Africa are 1-2%)
125
Serum Sickness
- Type 3 hypersensitivity (Bulky Ab-Ag complex depositing everywhere)
- a syndrome that is characterized by skin rash, joint stiffness, joint pain, facial and extremity swelling, and fever. Sometimes vomiting or respiratory distress happen. It may be mistaken for anaphylaxis.
- From Sulfonamides, penicillin allergies
126
Tuberculoid Leprosy
- Few (usually 1–3 lesions), localized, hypopigmented macules, plaques, and/or papules with well-defined, erythematous, and/or raised margins
- Lesions are dry, scaly, anhidrotic .
- Hair loss
- Hyperesthesia of the skin lesion is common and occurs early (hypoaesthesia of the skin develops in later stages).
- Nerve involvement occurs early but is localized, Asymmetric enlargement of one or many peripheral nerves, Acute neuritis does not occur.
- not systemic
127
Lepromatous Leprosy
- Multiple symmetrical macules, plaques, and/or nodules, generalized involvement of the skin
- Nodules on the face may coalesce → leonine facies
- Nodules may ulcerate
- Hypesthesia of the skin lesion is less common and occurs only in the late stages of the disease.
- Supraciliary and ciliary madarosis
- nerve involvement occurs late but is more extensive- Acral, distal, symmetrical anesthesia, Usually begins with stocking glove pattern that spreads proximally
- Systemic involvement includes: nasal stuffiness, epistaxis, hepatomegaly, nontender lymphadenopathy
128
Type 1 hypersensitivity
- immediate, anaphylactic and atopic
- IgE, CD4+, Th2 cells
- increases mast cells, eosinophils, and their mediators (IL4, IL5, IL13)
129
Type 2 hypersensitivity
- antibody mediated
- IgM, IgG against surface or extracellular matrix proteins
- Cellular destruction: opsonization, complement, ADCC
- inflammation: antibodies block or activate signaling (dysfunction)
130
Type 3 hypersensitivity
- Immune complex mediated
- Circulating antigen:antibody complex
-complement activation, neutrophil attraction, and lysozyme release
131
Type 4 hypersensitivity
- Delayed, T cell mediated
- CD4+, Th1, Th17, CD8+ cytotoxic T lymphocytes
- CD4+ Th cytokine mediated inflammation and macrophage and neutrophil activation
- Direct target cell killing (CD8+ CTLs)
132
What is leukemia?
- a group of malignant conditions of hematopoietic stem cells (myeloid or lymphoid) within the bone marrow
- Results in: uncontrolled proliferation of the malignant stem cell sin the marrow, leukemic cells replace the normal ones, which infiltrates into the peripheral blood and tissues throughout the body
133
What are the two major types of leukemia?
1. Myeloid
2. Lymphoid
- can present as acute or chronic
- many subtypes due to different mutations
134
What are the risk factors for leukemia?
- Chromosomal abnormalities (Down syndrome, chrom. instability syndromes)
- Ionizing radiation
- Chemicals (benzene)
- Alkylating agents (Busulfan)
- Chronic myeloproliferative diseases (polycythemia vera)
- Proxysmal nocturnal hemoglobinuria
- Cigarette smoking
- Immunodeficiency diseases (Wiskott-Aldrich)
135
What is the most common leukemia/ cancer in children?
- ALL (Acute lymphoblastic leukemia)
- also the most common cancer in children
136
What is the most common leukemia in people older than 60?
- CLL (Chronic lymphocytic leukemia)
137
What is the most common leukemia in people between 40-60?
- AML (acute myeloblastic leukemia)
- CML (chronic myelogenous leukemia)
138
What are the pathogeneses of leukemia?
- blocks stem cell differentiation
- monoclonal proliferation of cells before the block
139
Pathogenesis of acute leukemia
- block occurs at an early stage of stem cell development
140
Pathogenesis of chronic leukemia
- block occurs at a later stage in stem cell development
- some maturation in chronic leukemia
141
Acute leukemia overview
- poorly differentiated
- abrupt onset and aggressive with rapid progression
- high mortality in months
- peripheral smear: blasts + immature nucleolated cells)
- bone marrow: blasts >20%
142
Chronic leukemia overview
- well differentiated
- Gradual onset and indolent, slow progression
- survival for years
- high total leukocyte counts with more mature cells and few blasts
143
Lymphoma vs leukemia
- Leukemia: cancer arising primarily from the bone marrow from the stem cells
- lymphoma: a cancer arising primarily from the lymphoid cell in the lymph node
- NOTE: when lymphoma cells infiltrate the blood and bone marrow it is called the * leukemic phase of lymphoma and is treated like leukemia
144
Myeloproliferative syndromes (MPS)
145
Myelodysplastic syndromes (MDS)
146
Cancer of the bone marrow will show:
- excess blast cells
- anemia/ decreased RBC
- infections/ decreased WBC
- bleeding/decreased platelets
- bone pain
- splenomegaly
- hepatomegaly
- lymphadenopathy
147
White blood cell counts are always high in:
- chronic leukemia
- 90-95%: myeloid cells (left shift cells), basophilia --> CML
- 90%: lymphocytes --> CLL
148
AML has:
+ Auer rods and >20% myeloblasts
149
ALL has:
- Auer rods and >20% lymphoblasts
150
Variable white count in peripheral smear of leukemia
1. Leukemic: increased WBC count and presence of blasts
2. Subleukemic: blasts are present but no increase in WBC count
3. Aleukemic: no blasts seen in peripheral smear, WBC count is decreased
** both subleukemic and Aleukemic presentations on peripheral smear exam, bone marrow exam can be diagnostic (will show increased number of blast cells)
151
Sudan black B (SBB) and Myleoperoxidase (MPO) stain
Myeloblast stain for enzyme in granules of myeloid and monocytic cells, never found in lymphoid cells
152
PAS stain
Lymphoblasts stain for granular PAS pattern in lymphoblastic leukemia
153
Non-specific esterase (NSE) stain
Monoblasts stain for monocytic cells
154
Tartrate resistant acid phosphatase (TRAP) stain
Hairy cell leukemia stain
155
TdT: terminal deoxynucleotidyl-transferase stain
Immature T and B cell stain (Lymphoblasts)
156
Acid phosphatase stain
Stains for T cells, lymphoblasts which have a characteristic dot-like focus of intense positivity
157
Hairy cell leukemia
- uncommon (2%), indolent B cell neoplasm arising from memory B cells
- leukemic cells with fine, hair-like projections
- Pan-B cell markers (CD19 and CD20), surface immunoglobulin, and CD11c/CD103
- activating mutations in serine/threonine kinase BRAF
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Who is most likely to be diagnosed with Hairy cell leukemia?
- middle aged Caucasian males, median age: 55, M:F ratio: 5:1
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What symptoms are seen in hairy cell leukemia?
- Splenomegaly (90%), sometimes the only finding
- Pancytopenia (>50% from BM involvement, and splenic sequestration)
- LN involvement is rare (<10%), and hepatomegaly (20%)
- infection in 30% of patients- especially atypical mycobacterial infections, unexplained monocytopenia
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What has a DRY TAP on aspiration during a bone marrow biopsy?
Hairy cell leukemia
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Hairy cell leukemia prognosis
- very good
- HCL is extremely sensitive to gentle chemo: purine nucleosides, 2-choro-2-deoxyadenosine (complete remission in 85% of cases)
- BRAF inhibitors: excellent response in tumors that have failed conventional chemo
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Adult T cell leukemia/lymphoma
- Neoplasm of CD4+ T cells caused by a retrovirus: human T cell leukemia virus type 1, HTLV-1)
- infection is endemic in southern Japan, the Caribbean basin, and West Africa
- HTLV-1 can also cause transverse myelitis
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Symptoms of Adult T cell leukemia/lymphoma
- Skin lesions
- lymphadenopathy
- hepatosplenomegaly
- hypercalcemia
- malignant lymphocytes in the peripheral blood
- cells with multi-lobated nuclei (cloverleaf or flower cells)
- CD4, CD5 (IL2 receptor alpha chain) affected
- very aggressive, responds poorly to medication
- median survival time: 8 months
164
Microtubules are:
polymers of alpha and beta tubulin that act to separate replicated chromosomes during mitosis
165
Microtubule targeted drugs act in:
M phase and induce mitotic arrest in anaphase
- Vinca alkaloids and taxanes
166
Vinca alkaloids prevent:
microtubule assembly
167
Taxanes prevent:
microtubule disassembly
168
Vincristine
a natural vinca alkaloid produced by the periwinkle cantharanthus roseus plant. It has wide application against solid tumor and liquid cancers
169
Antimicrotubule drugs: Vincristine
- Class: vinca alkaloid, cell cycle specific (M phase)
- Indications: Leukemias, lymphomas, sarcomas, neuroblastomas, etc
- Mech of Action: inhibition of microtubule polymerization causing anaphase arrest
- administered via: IV
- excreted via: Biliary excretion/feces
- toxicities: neurotoxicity, constipation, myelosuppression
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Vinca Alkaloid drugs:
1. Vincristine (natural)
2. Vinblastine (natural)
3. Vinorelbine (synthetic)
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Paclitaxel
- a naturally occurring taxane produced by the Pacific Yew tree, Taxus brevifolia. It enhances microtubule polymerization and prevents depolymerization causing cells to die by mitotic catastrophe
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Antimicrotubule drugs: Paclitaxel
- Class: taxane antimicrotubule drug, cell specific (M phase)
- Indications: ovarian cancer, breast cancer, lung cancer (solid)
- Mech of Action: Stabilization of polymerized microtubules causing anaphase arrest
- administered via: IV
- excreted via: Biliary/fecal
- toxicities: myelosupression, infusion site reactions, sensory neuropathy
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Other microtubule stabilizing drugs like Paclitaxel
1. Docetaxel (natural)
2. Cabazitaxel (natural)
3. Ixabepilone (non-taxane microtubule inhibitor, not effluxed through p-glycoprotein)
4. Eribulin (non-taxane microtubule inhibitor, not effluxed through p-glycoprotein)
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Anthracycline antibiotics
- most commonly used antineoplastic drugs in clinical practice
- Based on structures of compounds derived from streptomyces peucetius
- Potential mechanisms:
1. inhibition of topoisomerase II
2. Intercalation in DNA, blocking DNA and RNA synthesis and causing DNA strand breaks (noncovalent interaction)
3. Generating ROS through enzyme catalyzed oxidation/reduction
4. Altering cell membrane fluidity
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Doxorubicin
- anthrocycline drug
- solid and hematological cancer effectiveness
- The red devil
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How does doxorubicin work on Topoisomerase II?
- it prevents the TopoII from re-ligating the transient break it makes during torsional strain relief.
- NHEK or HEJ occurs afterwards, potentially creating errors
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Anthracycline drugs: Doxorubicin
- Class: anthracycline antibiotic, cell cycle non-specific
- Indications: Breast cancer, lymphomas, sarcomas, lung, etc
- Mech of Action: topoisomerase II inhibition leading to double stranded DNA breaks
- administered via: IV
- excreted via: Biliary excretion in feces
- toxicities: Neurotoxicity, constipation, muelosuppression, ***delayed cardiac toxicity limits the lifetime of dose***
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Other anthracycline drugs like doxorubicin
1. Daunorubicin: used for AML, limited solid tumor use
2. Idarubicin: synthetic, AML induction
3. Epirubicin: Synthetic, breast/GI cancers
4. Mitoxantrone: anthracene used for breast/prostate
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Bleomycin
- metal binding domains and a DNA binding domain. It can bring ferrous iron and cuprous copper into close proximity with DNA in the nucleus, causing superoxide and hydroxyl radicals that cause DNA strand breaks
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Antibiotic drugs: Bleomycin
- Class: peptide antibiotic, cell cycle non-specific
- Indications: breast cancer, lymphomas, sarcomas, lung, etc
- Mech of Action: iron binding and DNA binding domains generate ROS that causes DNA breaks
- administered via: IM, also IV or intrapleural space
- excreted via: urine, the kidneys
- toxicities: dose limiting pulmonary toxicity, skin reactions
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Antimetabolites are:
analogs of intermediates of DNA synthesis. They inhibit specific enzymes and interrupt specific features of nucleic acid metabolism
182
antimetabolites are cell cycle specific in which phase?
S phase
183
Classes of antimetabolites include:
1. antifolates
2. fluorpyrimidines
3. deoxycytidine analogs
4. Purine antagonists
184
Which amino acids donate to the "one carbon pool"?
1. Serine (most important)
2. Glycine
3. Histidine
4. Tryptophan
185
Rapidly dividing cells have a high requirement for:
deoxynucleotides in order to support genome replication
186
What generates deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) in a methylation reaction?
Thymidylate synthase
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What is required to regenerate tetrahydrofolate (FH4) to sustain the thymidylate synthase pathway?
Dihydrofolate reductase
188
Methotrexate
Folate analog that acts as a competitive inhibitor (vmax same, km larger) of dihydrofolate reductase, restricting the folate pool available to support deoxynucleotide synthesis
189
Antifolate drugs: Methotrexate
- Class: Antimetabolite, folate analog, cell cycle specific (S phase)
- Indications: breast cancer, ALL lymphomas, head/neck
- Mech of Action: competitive inhibition of DHFR and blocking of deoxynucleotide synthesis
- administered via: ORAL, parenterally or IM
- excreted via: urinary excretion
- toxicities: myelosuppression, renal failure
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Other folate analog antimetabolites like methotrexate
1. Pemetrexed: mesothelioma, non-small cell lung cancer
2. Pralatrexate: relapsed T cell lymphoma
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5-fluorouracil
- a fluoropyrimidine, an analog of the pyrimidine base uracil
- acts as a non-competitive (decrease in Vmax, km unchanged) inhibitor of thymidylate synthase
- limits the availability of deoxypyrimidine nucleotides for genome replication
- used frequently for GI cancers
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How else can fluoridated nucleotides cause damage?
By being substrates of DNA and RNA polymerase
193
How 5-FU works:
5-FU + phosphoribosyl pyrophosphate (PRPP) --> nucleotide
5-FU-- thymidine phosphorylase + thymidine kinase --> nucleotide
-Creates fluoridated urine (FUTP and FdUTP) that can be incorporated into RNA and DNA, respectively
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Fluoropyrimidines: 5-FU
- Class: antimetabolite, fluoropyrimidine, cell cycle specific (S phase)
- Indications: colorectal, breast cancer, head/neck (solid)
- Mech of Action: non-competitive suicide inhibition of thymidylate synthase and depletion of deoxypyrimidines- misincorportation of fluoridinated nucleotides into RNA and DNA
- administered via: IV
- excreted via: urinary / kidneys
- toxicities: myelosuppression, mucositis, diarrhea, hand-foot syndrome
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other fluoropyrimidines like 5-FU
1. Capecitibine: orally bioavailable, breast and colon cancer
2. TAS-102: orally bioavailable, colorectal cancer
196
Cytarabine
an analog of the pyrimidine nucleoside deoxycytidine. Cytarabine is phosphorylated to cytarabine triphospgate by cellular kinases. It then inhibits DNA polymerases alpha and beta. If incorporated into DNA, it will create double stranded breaks during next round of replication
197
Deoxycytidine drugs: Cytarabine
- Class: antimetabolite, deoxycytodine analog, cell cycle specific (S phase)
- Indications: hematologic malginancies only (NO solid tumors)
- Mech of Action: incorporation of cytarabine nucleotides into DNA
- administered via: IV
- excreted via: urinary/kidney
- toxicities: myelosupression, nausea, vomiting, cerebellar ataxia
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Other deoxycytidine analog like cytarabine
1. Gemcitabine: fluorinated deoxycytidine analog with broad activity against solid tumors
199
Fludarabine
- A purine analog of adenosine. Has -arabinose rather than ribose sugar, and a fluorinated base
- it is used to treat various lymphomas and leukemias. pro-drug form is fludarabine phosphate with a phosphate on the 5' hydroxyl group
200
Fludarabine is phosphorylated to the triphosphate form by:
intracellular kinases
- this form inhibits DNA polymerases and repair enzymes, causing DNA breaks and cell death
201
Other purine antagonists like Fludarabine
1. Cladribine
2. Clofarabine
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Purine Antagonist drugs: Fludarabine
- Class: antimetabolite, purine antagonist, cell cycle specific (S phase)
- Indications: leukemias and lymphomas (blood cancers)
- Mech of Action: inhibition of nucleic acid metabolism
- administered via: IV and orally available
- excreted via: urinary/kidney
- toxicities: life threatening autoimmune reactions, hemolytic anemias
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Alkylation is:
the transfer of carbons. Alkylation of DNA can occur naturally from endogenous compounds, and from alkylating agents in our environment
204
The goal of treating a cancer patient with alkylating agents is to:
kill cancer cells by causing cytotoxic DNA damage and mutations
- alkylating agents are: cell cycle non-specific (though cancer cells are more susceptible in G1 and S phases
205
The major site of alkylation by therapeutic agents are:
1. N7 of guanine
2. O6 of guanine
3. potentially also the phosphodiester backbone of DNA
206
How can cancer cells become resistant alkylating agents?
Elevated DNA repair activity (MGMT, AlkB)
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Nitrogen mustards: mechlorethamine
Class: alkylating agent, cell cycle, non-specific
Indications: Hodgkin’s lymphoma, non-Hodgkin’s lymphoma
Mech of action: inter- and intra- strand cross-linking of DNA inhibits DNA replication and causes DNA damage
Absorption via: IV
Excretion: urine/kidneys
Toxicities: myelosuppression: anemia, thrombocytopenia, neutropenia
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The nitrogen mustard cyclophosphamide requires activation by:
Hepatic enzymes to form the cytotoxic, cross-linking agent phosphoramide mustard
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What is a mechanism of cyclophosphamide resistance?
Expression of aldehyde dehydrogenase
210
Phosphoramide mustard alkylates what?
N7-guanines, cross-linking nearby bases
211
Nitrogen mustards: cyclophosphamide
Class: alkylating agent, cell cycle, nonspecific
Indications: breast, cancer, non-Hodgkin’s, informer, CLL
Mech of action: inactive until metabolized by the liver. Active form makes inter-and intra-strand cross-linking of DNA inhibits DNA replication and causes damage.
Absorption via: orally
Excretion: urine/kidneys
Toxicities: myelosuppression and bladder toxicity
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Melphalan
Combines the essential amino acid phenylalanine with a nitrogen mustard. The drug takes advantage of endogenous amino acid transporters, and is bioavailable orally.
213
Nitrogen mustards: melphalan
• Class: alkylating agent, cell cycle, nonspecific
• Indications: multiple myeloma, breast, cancer, ovarian cancer, retinoblastoma
• Mech of action: forms inter-and intra-strand, cross-links inhibiting DNA replication and causes DNA damage
• Absorption via: oral, decreased with food
• Excretion: urine, feces
• Toxicities: myelosuppression
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Nitrosourea
• alkylating agents, derived from nitrosourea source. Siri, lipid soluble, able to penetrate the blood brain barrier. Prodrug.
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Carmustine
• BCNU, forms, interstrand cross-links between guanines and cytosines
• spontaneously degrees into fragments that alkylate DNA and carbamoylyate proteins (O6 of guanine is the worst)
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Nitrosoureas: carmustine
• Class: alkylating agent, cell cycle, nonspecific
• Indications: brain, tumors, Hodgkin’s lymphoma, non-Hodgkin’s, lymphoma, multiple myeloma
• Mech of action: forms interstrand GC cross links, carbomoylates proteins
• Absorption via: IV
• Excretion: urine, exhaled as CO2
• Toxicities: delayed myelosuppression, infertility, secondary malignancies
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Lomustine
A nitrosourea with a similar mechanism of action as carmustine. It is lipid, soluble crosses the BBB and can be used to treat bring answers. *ORALLY AVAILABLE
218
Lomustine spontaneously degrades to chloroethylene ion, which:
Alkylates O6 of guanine. Subsequent reactions lead to interstrand ethyl crosslink between N1 of guanine and N3 of cytosine
219
Nitrosoureas: Lomustine
• Class: alkylating agent, cell cycle, nonspecific
• Indications: brain tumors, Hodgkins lymphoma, non-Hodgkin’s lymphoma
• Mech of action: forms interstrand G-C cross-links
• Absorption via: oral-complete
• Excretion: urinary/kidneys
• Toxicities: myelosuppression, sterility, secondary malignancies
220
Streptozocin
• A nitrosourea bonded to a glucose molecule. Produced by streptomyces achromogenes
• localize to islet cells of the pancreas— can induce type one diabetes and cause hyper/hypoglycemia
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Nitrosoureas: streptozocin
• Class: alkylating agent, cell cycle, nonspecific
• Indications: pancreatic islet cell cancer, carcinoid tumors
• Mech of action: forms interstrand G-C crosslinks
• Absorption via: IV
• Excretion: urinary/kidneys
• Toxicities: dose limiting renal toxicity mild myelosuppression, hyper/hypoglycemia
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What was the first metal base drug applied to cancer therapy?
Cisplatin
223
How does cisplatin enter the cell?
Copper transporters or by diffusion. Binds preferentially to the N7 of guanine in the nucleus.
224
Platinum agents: cisplatin
• Class: platinum agent, cell cycle nonspecific
• Indications: testicular, cancer, ovarian, bladder
• Mech of action: forms intrastrand G-G crosslinks
• Absorption via: IV or intraperitoneal
• Excretion: urinary/kidneys
• Toxicities: those limiting renal toxicity, myelosuppression, peripheral neuropathy, sterility
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Carboplatin
A second generation platinum agent with the same mechanism of action of cisplatin: intrastrand G-G cross-links. Has fewer toxicities
226
Platinum agents: carboplatin
• Class: platinum agent, cell cycle nonspecific
• Indications: ovarian, germ, cell, tumors, head/neck cancers
• Mech of action: forms, intrastrand G-G cross-links
• Absorption via: IV
• Excretion: urinary/kidneys
• Toxicities: myelosuppression, renal, toxicity, peripheral neuropathy, sterility
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Oxaliplatin
• third-generation, platinum agent
• makes a bulkier DNA adduct and can make intrastrand G-G, G-A cross-links and interstrand G-C crosslinks
228
Platinum agents: oxaliplatin
• Class: platinum agent, cell cycle nonspecific
• Indications: colorectal cancer, pancreatic cancer
• Mech of action: forms intrastrand G-G and G-A cross-links, interstrand G-G
• Absorption via: IV only
• Excretion: urinary/kidneys
• Toxicities: peripheral sensory neuropathy, and other neural toxicities, myelosuppression
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Alkylating antibiotic: Mitomycin C
• Class: alkylating antibiotic, cell cycle nonspecific
• Indications: gastric, pancreatic, breast, bladder
• Mech of action: forms interstrand G-C
• Absorption via: IV only
• Excretion: hepatobiliary is excretion in feces
• Toxicities: myelosuppression, injection site injury
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Nonclassical alkylating agents: dacarbazine, procarbazine, temozolomide
• bio activated to methyl diazonium ion in the body. Transfers, muscle groups to guanine on O6, N7, and N3-adenine —> causes C-T mutation
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Dacarbazine
• undergoes, metabolism by cyp450 enzymes to form methyl diazonium ion
• transfer is methyl groups to guanine’s O6 to form O6 methyl guanine
232
Nonclassical alkylating agents: Dacarbazine
• Class: alkylating agent, cell cycle nonspecific
• Indications: melanoma, Hodgkin’s lymphoma, soft tissue, carcinoma, neuroblastoma
• Mech of action: forms O6-MG
• Absorption via: IV preferred, oral route is slow and variable
• Excretion: urinary, kidneys
• Toxicities: myelosuppression, N/V, injection site injury, mutagenic and carcinogenic secondary malignancies
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Nonclassical alkylating agents: procarbazine
• Class: alkylating agent, cell cycle nonspecific
• Indications: melanoma, Hodgkin’s lymphoma, soft tissue sarcoma, neuroblastoma
• Mech of action: forms O6-MG and oxidative damage, weak MAOI
• Absorption via: complete absorption in GI tract: oral
• Excretion: urinary/kidneys
• Toxicities: myelosuppression, nausea and vomiting, secondary malignancies (AML)
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Temozolomide
• An alkylating agent used to treat astrocytomas and gliomas
• non-enzymatically converted to 4-amino-5-imidazole-carboxamide (AIC) and methyl diazonium cation —> reacts with O6 and N7 on guanine, making methyl guanine
235
Nonclassical alkylating agents: Temozolomide
• class: alkylating agent, cell cycle nonspecific
• indications: melanoma, Hodgkin’s lymphoma, soft tissue sarcoma, neuroblastoma
• mech of action: forms O6-MG
• absorption via: Complete oral absorption
• excretion: urinary/kidneys
• toxicities: myelosuppression, nausea and vomiting, mutagenic and carcinogenic
236
Resistance to alkylating agents can occur through:
1. Decreased intake or increased efflux of the drug
2. Metabolism through alternative pathways (aldehyde dehydrogenase for cyclophosphamide)
3. Altered DNA repair pathways: increase in activity of pathways that repair lesions or decrease in activity of pathways that stall replication in cause apoptosis
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Non Hodkgin's lymphoma (NHL)
- 60% of adult lymphomas
- 80% or more are derived from the germinal follicle
- second most common cancer in AIDS
- 1/3 arise from extranodal sites
- median age: 50 years
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What are the childhood NHLs?
- T cell lymphoblastic lymphoma
- Burkitt lymphoma
- more aggressive in children than adults
- mutation produces a block in the development of T/B cell
239
Risk Factors for NHL: viruses
1. EBV (burkitts)
2. HTLV-1 (adult T cell lymphoma/leukemia)
3. Hep C (HCV, B cell lymphoma)
240
Risk factors for NHL: autoimmune disease
1. Sjorgren syndrome (salivary gland and GI lymphoma)
2. Hashimoto thyroiditis (malignant thyroid lymphoma)
241
Risk Factors for NHL: immunodeficiency
1. Helicobacter pylori (low grade malignant lymphoma of stomach)
2. Chromosome instability syndromes (BLOOM, AIDS)
3. High dose radiation: risk of hodgkin lymphoma
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Acute lymphoblastic leukemia/ lymphoblastic lymphoma (ALL)
- aggressive tumors composed of immature lymphocytes (lymphoblasts) predominantly in children and young adults (MANY lymphoblasts in peripheral blood and marrow)
- pre B cell: 80% of childhood leukemia, peak at 4 years
- pre T cell: mostly young adult males, 15-20 years
- T cell ALL can present as mediastinal mass (presenting as SVC-like syndrome)
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Pathogenesis of ALL
- TdT+, CD19+, CD10+, CD2+, CD7+ (markers of pre-T and pre-B cells)
- translocation t(12;21) better prognosis
- translocation t(9;22) worse prognosis (BCR-ABL fusion gene)
244
ALL is associated with what mutation?
NOTCH1 mutations
245
Small lymphocytic lymphoma/ Chronic lymphocytic leukemia (SLL)
- age > 60 years, most common adult leukemia
- CD20+, CD23+, CD5+ B cell neoplasm
- INCREASED BCL2
- progresses SLOWLY, indolent, asymptomatic
- infection secondary to hypogammaglobinemia
-SMUDGE CELLS (broken lymphocytes) in periphery
- autoimmune hemolytic anemia
- Richter transformation
246
Richter transformation
CLL/SLL transformation into an aggressive lymphoma (DLBCL)
247
SLL/CLL morphology
- diffuse effacement of lymph nodes
- sheets of small lymphocytes and scattered larger, actively dividing cells (proliferation centers-- pathognomonic)
- bone marrow, spleen, and liver involved
- smudge cells
248
Follicular lymphoma
- adult cancer- indolent and painless, waxing and waning course of lymphadenopathy
- translocation t(14;18) of heavy chain Ig (14) with BCL2 (18) causing an overexpression of BCL2 protein contributing to proliferation
- CD19, CD20, CD10 and BCL6 + on the surface
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Morphology of follicular lymphoma
- nodular proliferation
- tumor cells resemble normal germinal center B cells (small with angular cleaved nuclei -- CENTROCYTES)
- large cells (centroblasts) minor compnent
250
40% of follicular lymphoma patients progress to:
DLBCL with median survival less than one year
251
Diffuse Large B cell Lymphoma (DLBCL)
- usually adults, 20% in children, most common NH lymphoma in adults
- mutation in BCL2 and BCL6 , BCL6 more common
252
DLBCL morphology
- Neoplastic B cells are large (3-4x normal lymphocytes)
- diffuse pattern of growth--> round to oval nuclei with dispersed chromatin and distinct nucleoli
- Pan-B cell antigens (CD19 and CD20)
253
Immunodeficiency-associated large B cell lymphoma
- in AIDS, iatrogenic immunosuppression (transplant recipients), and elderly
- EBV- critical pathogenic role
- restoration of T cell immunity may lead to regression
254
Primary effusion lymphoma
- subtype of DLBCL
- may arise within the pleural cavity, pericardium, or peritoneum
- patients with advanced HIV infections or older adults
- associated with Kaposi sarcoma (HHV8)
255
Clinical features of DLBCL
- age around 60 years
- rapidly enlarging, symptomatic mass at one or several sites
- extra-nodal presentations common (GIT, Brain)
- usually NO bone marrow involvement
- treatment: intensive combo of chemo and anti-CD20 immunotherapy
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Burkitt lymphoma
-Endemic in parts of Africa (belt)
- Translocation t(8;14), of c-myc (8) and heavy chain Ig (14) causing dysregulation and overexpression of MYC
- EBV present in 25% of HIV-associated and 15-20% of sporadic
- surface IgM, CD19+, CD20+, CD10+, BCL6 -germinal center B cell origin
- NO expression of BCL2
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Morphology of Burkitt lymphoma
-Starry sky, sheets of lymphocytes with interspersed "tingible body" macrophages
- BM aspirate: basophilic/amphophilic royal blue cytoplasm containing small, lipid-filled vacuoles
- high mitotic index and contains numerous apoptotic cells
258
Clinical features of Burkitt lymphoma
- Children, young adults
- 30% of childhood NHL
- maxillary/madibular masses
- abdominal tumors involving bowel, retroperitoneum, and ovaries in north America
259
Mantle cell lymphoma
- adult males most common
- from naive B cells found in the mantle zones of normal lymphoid follicles
- translocation t(11;14) of cyclin D (11) and heavy chain (Ig)
- CD5+, pan-B cell antigens (CD19+, CD20+), IgM and IgD surface antigens
- Gi- mucosal lymphomatoid polyposis, aggressive cancer, presenting in late stage disease
260
Clinical features of mantle cell lymphoma
-fatigue, lymphadenopathy
- generalized disease involving bone marrow, spleen, liver, and GI tract
- poor prognosis (3-5 years)
- distinguishable from SLL/CLL by absence of proliferation centers and presence of Cyclin D1
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Extranodal marginal zone lymphomas (MALT-omas)
-indolent B cell lymphoma arising from memory B cells
- epithelial tissues affected (stomach, salivary, small and large bowel, lungs, orbit, and breast)
- associated with autoimmune disorders (Sjogran syndrome, hashimoto thyroiditis, H. pylori)
- Translocation, t(11;18) involving the MALT1 and IAP2 genes is highly predictive of the failure of gastric tumors to respond to abx
262
Precursor T cell lymphoblastic leukemia/lymphoma
- 40% childhood lymphomas
- of thymic origin, primarily involves the anterior mediastinal and cervical nodes (lump in chest presentation)
- aggressive
-NOTCH mutations (T cell version of ALL)
263
Mycosis Fungoides and Sezary syndrome
- Tumors of neoplastic Cd4+ T cells, aka cutaneous T cell lymphoma
- indolent tumors, survival is 8-9 years
- Phases include: patch-->plaque--> tumor , with tumor leading to sezary syndrome and a poor prognosis (1-3 years)
- pautrier microabscesses
264
Pautrier microabscesses
- T cells with cerebriform appearance (marked infolding of the nuclear membranes) that infiltrate the epidermis and dermis
- seen in Mycosis fungoides
265
Sezary syndrome
- characterized by:
1. generalized exfoliative erythroderma
2. tumor cells (sezary cells) in the PERIPHERAL BLOOD leading to Mycosis fungoides with a leukemic phase
266
Anaplastic large cell lymphoma
- arises from cytotoxic T cells
- rearrangements in ALK (anaplastic lymphoma kinase) gene on chr 2p23 --> + ALK
- children and young adults with LN and soft tissue disease
- aggressive, but there is targeted therapy for the +ALK
267
Anaplastic large cell lymphoma morphology:
- clustering around venules and infiltration of lymphoid sinuses
- mimics metastatic carcinoma
- HALLMARK CELLS: abundant basophilic cytoplasm, prominent golgi zone, and lobulated nucleus (horseshoe or embyroid) with nuclear lobes surrounding the golgi region
- CD8+
- translocation, t(2;5) Alk gene fusion)
268
Large granular lymphocytic leukemia
1. T cell
- mild-moderate lymphocytosis, splenomegaly, lymphadenopathy, or hepatomegaly
- CD3+ve
2. NK cell
- no lymphocytosis or splenomegaly
- CD3-ve, CD56+ve
- aggressive
- acquired mutations in the transcription factor: STAT3
269
Large granular lymphocytic leukemia morphology
- neutropenia and anemia
- large lymphocytes with abundant blue cytoplasm and a few coarse azurophilic granules on peripheral smear
- Felty syndrome-- LGLL as an underlying cause
270
Felty syndrome
Triad of rheumatoid arthritis, splenomegaly, and neutropenia
271
Extranodal NK/T cell lymphoma
- aggressive tumor, usually derived from NK cells that is STRONGLY associated with EBV infection
- responds well to radiation therapy but is resistant to chemotherapy
272
Prognosis of NHL depends on
1. aggressive, respond well to treatment (Mantle cell, Burkitt, DLBCL)
2. Indolent, respond poorly to treatment but longer course (SLL, follicular, marginal zone, Waldenstom's macroglobinemia)
3. Staging (Ann Arbor) 3-4 is worst
4. High LDH levels = poor prognosis
273
When growth factor binds EGFR:
receptor chains dimerize--> activation of cytoplasmic tyrosine kinase domains --> phosphorylated tyrosines for docking sites for many SH2 domains --> aggregation of proteins at the plasma membrane --> transduction of signals to the nucleus
274
EGFR is:
1. a homodimer of ErbB1
2. a heterodimer of ErbB1/ErbB2
275
Pathway of activation of EGFR/Ras
Ras + GDP (off) --> Ras + GTP (on) --> activates MAP kinase pathways --> increase Myc and AP-1 --> increase expression of growth promoting genes (such as Cyclin D1)
Ras + GTP --> PI3K --> Akt --> Raf --> MEK --> ERK --> cell proliferation
276
Growth factor binding to EGFRs causes:
- a conformational change that exposes dimerization domains which activates tyrosine kinase
277
EGFR inhibitors: Gefitinib
- Class: EGFR small molecule inhibitor
- indications: metastatic NSCLC with EGFR mutations
- mech of action: inhibitions of EGFR's cytoplasmic tyrosine kinase domain
- Absorption: slow oral
- exretion via: biliary/feces
- toxicities: elevated blood pressure, eyelash trichomegaly
278
Other EGFR small molecule inhibitors:
1. Erlotinib (hair repigmentation in NSCLC)
2. Afatinib
3. Osemertinib (prolonged QT intervals)
279
EGFR inhibitor: Cetuximab
- Class: monoclonal antibody EGFR inhibitor
- indications: colorectal cancer with wild type Ras
- mech of action: inhibition of EGFR's extracellular ligand binding domain, preventing dimzerization and activation
- Absorption: IV (monoclonal always IV)
- excretion via: unknown
- toxicities: infusion related symptoms, fever, chills, HA, hypotension
280
Other monoclonal EGFR inhibitors
1. Panitumumab: pulm toxicity risk
2. Necitumumab: cardio pulm arrest risk
281
Which ErbB family member propagates a proliferative signal without any ligand?
ErbB2 (HER2)
282
What are the monoclonal antibodies that target ErbB2's extracellular doman?
1. Trastuzumab
2. Pertuzumab
-- Lapatinib, neratinib, and pazopanib are small molecule tyrosine kinase inhibitors
283
PI3K is a heterodimer of what?
p85 (regulatory) and p110 (catalytic) subunits. Mutations in either enzyme can hyperactivate it
284
What mutation decreases how well trastuzumab works?
PI3K activating mutations
285
Her2 inhibitors: Trastuzumab
- Class: monoclonal antibody ErbB2 (Her2) inhibitor
- indications: Her2 overexpressing breast cancer
- mech of action: Inhibition of ErbB2's extracellular domains
- Absorption: IV only
- excretion via: unknown
- toxicities: Infusion related symptoms, fever, chills, HA, hypotension, CARDIAC TOXICITY, esp when combined with anthracycline
286
ErbB2 inhibitors: Lapatinib
- Class: small molecule ErbB2 (Her2) tyrosine kinase inhibitor
- indications: Breast cancer
- mech of action: inhibition of ErbB2's intracellular tyrosine kinase domains
- Absorption: oral
- excretion via: hepatic/feces
- toxicities: Diarrhea common, cardiac toxicity, myelosuppression
287
BCR-ABL fusion gene
- translocation, t(9;22) fusing B cell receptor gene with ABL kinase gene causing hyperactive Abl kinase that sustains proliferation
- leads to CML and other B cell malignancies
- promotes hallmarks of cancer such as:
1. Resisting cell death (Bcl2)
2. sustaining proliferation signals (MAPK and JAK/STAT)
3. activating invasion and metastasis (FAK)
288
Imatinib
- small molecule inhibitor that was selected to only have activity against Bcr-Abl fusion protein
- binds in the ATP binding pocket of the Abl kinase domain
- off target effects are minimized because only malignant cells express the fusion gene
289
Bcr-Abl inhibitors: imatinib
- Class: small molecule Bcr-Abl tyrosine kinase inhibitor
- indications: CML, acute lymphoblastic leukemia
- mech of action: Competes with ATP for binding at catalytic site
- Absorption: orally
- excretion via: hepatic/feces
- toxicities: nausea and vomiting (relieved by food). fluid retention (CHF rare)
290
Other Bcr-Abl inhibitors used in CML
1. Bosutinib
2. Ponatinib
- mutation of the fusion gene is a common cause of resistance to imatinib: both of these are used for imatinib resistance because they also inhibit other tyrosine kinases (ex. SRO family kinases)
291
Bruton Tyrosine Kinase (BTK)
a driver for some B cell lymphomas, and can be targeted with small molecule inhibitors like ibrutinib (used in CLL)
292
BTK inhibitors: Ibrutinib
- Class: small molecule bruton kinase inhibitor
- indications: CLL, mantle cell lymphoma
- mech of action: irreversible covalent bonding with cysteine at BTK active site
- Absorption: orally
- excretion via: Hepatic/feces
- toxicities: Bleeding: echymoses, GI or hematuria, myelosuppression, renal toxicity, secondary malignancies
293
What is a newer treatment combo for CLL?
pairing BTK inhibition (ibrutinib) with Bcl-2 antagonist (venetoclax)
294
Triple negative breast cancer
- ER -, PR-, HER2-
- high grade, high Ki67 index
- NST histology--> metaplastic, adenoid cystic, medullary-like, and secretory)
- poor prognosis
295
HER2 enriched (non luminal) breast cancer
- ER-, PR-, HER2+
- high grade, high Ki67 index
- NST histology--> aggressive disease but responds to targeted therapies
- intermediate prognosis
296
Luminal B-like, HER2+ breast cancer
- ER+, lower ER and PR expression than luminal-A
- HER2+ higher grade
- High Ki67 index
- NST and pleomorphic histology--> responds to targeted therapies
- intermediate prognosis
297
Luminal B-like, HER2- breast cancer
- ER+, lower ER and PR expression than luminal-A
- HER2- higher grade
- High Ki67 index
- high risk GES: NST histology --> micropapillary and lobular pleiomorphic histology
- intermediate prognosis
298
Luminal A-like breast cancer
- Strongly ER+ and PR+, HER2-
- low proliferation rates
- low grade
- low Ki67 index
- low risk GES, NST histology --> tubular cribriform and classic lobular histo
- good prognosis
299
Testosterone and estrogen are synthesized from:
cholesterol in the ovaries/testes
300
The adrenal gland synthesizes:
sex steroid precursors, DHEA and androstenedione
301
What controls the steroid hormone synthesis?
hypothalamic-pituitary-gonadal axis
hypothalamus releases GnRH --> stimulates anterior pituitary --> releases LH and FSH --> gonadal tissues express the genes necessary for the conversion of cholesterol to the steroid hormones
- pulsatile release, GnRH is controlled by feedback inhibition
302
Steroids bind their receptors:
intracellularly, causing translocation to the nucleus, dimerization, and binding of the dime to steroid response elements (SRE) in gene promoters. Co regulator proteins then recruit RNA polymerase II to initiate transcription
303
Hypothalamic-pituitary-gonadal axis in males
FSH--> Sertoli cells--> spermatogenesis
LH--> Leydig cells--> steroid biosynthesis (testosterone)
304
What is the key enzyme for cholesterol being converted to testosterone in Leydig cells
17-alpha-reductase (P450 cyp17)
305
in prostate, testosterone is converted to dihydrotestosterone by
5-alpha-reductase. Dihydrotestosterone is a potent activator of the androgen receptor
306
What are used in treatment of benign prostate hyperplasia?
5-alpha-reductase inhibitors
307
endocrine therapy in males: Degarelix
- Class: peptide GnRH antagonist
- Indications: Prostate cancer
- Mech of action: blocks activation of anterior pituitary cells that release LH and FSH
- Absorption: Subcutaneous
- Excretion: feces
- Toxicities: hot flashes, decreased libido, impotence
308
Endocrine therapy in males: Leuprolide
- Class: peptide GnRH superagonist
- Indications: prostate cancer
- Mech of action: Blocks activation of anterior pituitary cells that release LH and FSH
- Absorption: subcutaneous or IM
- Excretion: urinary
- Toxicities: hot flashes, decreased libido, impotence, tumor flare (because at the start of agonism tumor may get worse)
309
Endocrine therapy in males: Abiraterone
- Class: 17-alpha-reductase inhibitors
- Indications: prostate cancer
- Mech of action: Blocks the action of 17-alpha-reductase, a CYP P450 enzyme required for testosterone synthesis in Leydig cells
- Absorption: oral
- Excretion: Feces
- Toxicities: fatigue, mild nausea
310
Endocrine therapy in males: Enzalutamide
- Class: antiandrogen
- Indications: prostate cancer
- Mech of action: Competitive inhibition of androgen receptor, reduced transcription of pro-growth
- Absorption: oral
- Excretion: feces
- Toxicities: fatigue and weakness, skeletal and muscle pain
311
Hypothalamic-pituitary-gonadal axis in females
LH--> stimulation of receptors on ovarian cells--> 17-alpha-reductase expression increases in thecal cells and aromatase expression is increased in granulosa cells --> 17-beta-estradiol (estrogen) is produced
312
What controls the proliferation of mammary epithelial cells?
Estrogen
313
What converts cholesterol to testosterone using alpha-17-reductase in females?
ovarian thecal cells
314
what cells convert testosterone to estrogen?
aromatase expressing granulosa cells
315
Endocrine therapy in females: Tamoxifen
- Class: non-steroidal estrogen receptor modulator
- Indications: hormone receptor positive breast cancer (luminal), ER+, PR+
- Mech of action: estrogen receptor competitive mixed agonist antagonist
- Absorption: oral
- Excretion: feces
- Toxicities: menopause symptoms, peripheral edema
316
Endocrine therapy in females: Fulvestrant
- Class: steroidal selective estrogen receptor downregulator
- Indications: breast cancer, ER+, PR+
- Mech of action: estrogen receptor competitive antagonist, causes ER degradation (sometimes in combo with pablociclib)
- Absorption: IM injection 1x a month
- Excretion: feces
- Toxicities: weakness, hot flashes, arthralgias
317
Endocrine therapy in females: Letrozole
- Class: non-steroidal aromatase inhibitor
- Indications: breast cancer extended adjuvant therapy
- Mech of action: Competitive inhibition of aromatase and blocking estrogen synthesis (sometimes in combo with pablociclib)
- Absorption: Oral
- Excretion: feces
- Toxicities: arthralgias, hot flashes (less common than with antiestrogens)
318
The biologically active form of Vitamin A is:
all-trans-retinol, the alcohol trans-retinol can be converted to: aldehyde, carboxylic acid, ester with fatty acid
- retinoic acid is an important regulator of the immune system
319
The retinoic acid receptor functions as:
a ligand activated transcription factor (that forms heterodimers to initiate transcription of genes with retinoic acid response elements in their promoters
320
In the absence of ligand, the retinoic acid receptor (RAR) forms a complex with:
Histone deacetylase (HDAC) that represses transcription
321
In the presence of all-trans retinoic acid (ATRA), the complex activates:
transcription by acetylating histones and initiating trnascription
322
Retinoic acid receptor activation is important for:
hematopoiesis and differentiation of myeloid cells
- in its absence, myeloid progenitor cells proliferate rapdily and never differentiate
323
Acute promyelocytic leukemia
-Translocation t(15;17), retinoic acid receptor (RAR-alpha) and the PML protein
- this translocation protein acts as a transcriptional repressor
324
APL therapy: tretinoin
- Class: all trans retinoic acid receptor agonist
- Indications: acute promyelocytic leukemia (PML) with t(15;17)
- Mech of action: activation of the PML-RAR fusion protein stimulates differentiation of myeloid precursors
- Absorption: orally
- Excretion: fecal (2/3) and urinary (1/3)
- Toxicities: hypervitaminosis A: HA, conjunctivitis, rash, peripheral edema
325
PARP1
- critical for many DNA repair mechanisms, it recognizes and binds sites of DNA damage, It then adds poly ADP-ribose to itself and recruits DNA damage repair enzymes
** the ADP-ribose comes from NAD+
326
What is critical for homologous repair of double stranded DNA breaks?
- BRCA1 and BRCA2
- mutations result in breast and ovarian cancers
327
What do pharmacological PARP inhibitors do?
The "trap" PARP at the site of single stranded DNA breaks, but prevent repair. The unresolved single strand breaks become double stranded breaks -- that cannot be recovered via homologous recombination by BRCA1/2 and results in more error prone mechanisms --> Synthetics lethal treatment strategy
328
PARP inhibitors: Olaparib
- Class: PARP inhibitor
- Indications: breast and ovarian cancers with known or suspected BRCA1/2 mutations
- Mech of action: Trapping PARP on DNA causes double stranded breaks and synthetic lethality in the absence of BRCA 1/2
- Absorption: oral
- Excretion: 1/2 feces, 1/2 urine
- Toxicities: fatigue, URIs
329
Treatment for CLL
BTK inhibition (ibrutinib) with a Bcl2 antagonist (venetoclax)
330
What is the function of Bcl2?
- an apoptotic protein that functions to block cytochrome C release from the mitochondria
331
Apoptotic stimuli induce BH3-only proteins that:
form a complex with BAX/BAK that induces mitchondrial permeability and apoptosis
-- Bcl2 acts as a "sink" for BH3-only proteins and raises the apoptotic threshold
332
Bcl2-antagonist: Venetoclax
- Class: Small molecule Bcl2 antagonist
- Indications: Chronic lymphocytic leukemia
- Mech of action: acts as a BH3-only protein mimetic to lower apoptotic threshold
- Absorption: Oral
- Excretion: hepatic/feces
- Toxicities: tumor lysis syndrome, myelosuppression
333
Clinical finding in acute leukemia
- Abrupt onset of signs and symptoms
- signs of bone marrow failure, fever, bleeding, fatigue
- signs of metastatic disease (hepatosplenomegaly, painless lymphadenopathy, bone pain and tenderness)
- CNS, testicle involvement especially in ALL
- skin involvement (T cell leukemias)
334
Physical findings of acute leukemia
- weakness, pallor, fatigue
- infections causing fever (functionally incompetent WBCs)
- Easy bleeding/bruising
- Bone pain (periosteal infiltration)
- bleeding from venipuncture and orifices (DIC) due to release of thromboplastin (AML M3)
335
What causes gum hyperplasia?
AML M4 and M5 - infiltration
336
What causes rash and skin nodules?
Adult T cell leukemia
337
What has CNS and testicular infiltration?
ALL
338
What are the signs of bone marrow failure?
1. neutropenia: infections, fever
2. Anemia: fatigue, pallor
3. Thrombocytopenia: bleeding
339
Lab findings in acute leukemia
- variable peripheral WBC count (<10,000 and >100,000), blast cells usually present
- normocytic to macrocytic
- thrombocytopenia (usually <100,000)
- Bone marrow findings: MOST IMPORTANT FOR DIAGNOSIS: Hypercellular with >20% blast cells, usually completely replaced with blast cells
340
Acute myeloid leukemia
- older adults (>50)
- fatigue, pallor, abnormal bleeding, infections
- can present as discrete tissue mass (granulocytic sarcoma)
341
Acute myeloid leukemia risk factors:
- Genetic (Down syndrome, Turner, Klinefelter)
- Chemical/drugs (benzene, alkylating agents)
- Ionizing radiation, MDS
- Cytogenetic abnormalities (mutations on chromosome 8, translocation t(8;21)
342
HSC--> Myeloid SC--> Erythroblast-->
AML-M6 (acute erythroleukemia)
343
HSC--> myeloid SC--> megakaryoblast-->
AML-M7 (acute megakaryocytic leukemia)
344
HSC--> myeloid SC--> myeloblast-->
AML-M0-M4 (M0: minimally differentiated AML, M4: acute myelomonocytic leukemia, inv(16))
345
HSC--> myeloid SC--> monoblast-->
AML-M4-M5 (M4: acute myelomonocytic leukemia, M5: acute monocytic leukemia)
346
HSC--> Lymphoid SC--> pre-B lymphocyte-->
B-ALL-CD10+ve
347
HSC--> lymphocyte SC--> Pro-T lymphocyte-->
T-ALL
348
AML with recurrent genetic abnormalities:
- t(8;21)(q22;q22)(AML/ETO) *favorable prognosis
-inv(16), or t(16;16)(p13;q22) (CBF/MYH11)- M4eo *favorable prognosis
- t(15;17)(q22;q21) *intermediate prognosis
- (11q23) (MLL fusion gene) - poor prognosis
349
AML with multilineage dysplasia, MDS like features, poor prognosis:
- AML plus dysplasia (>50% of cells of 2 or more myeloid lines)
350
AML therapy-related
- very poor prognosis
- Alkylating agent, radiation therapy, topoisomerase II inhibitor
351
FAB classification of AML:
M0: minimally differentiated AML
M1: AML without maturation
M2: AML with maturation, t(8;21)
M3: acute promyelocytic leukemia, t(15;17)
M4: acute myelomonocytic leukemia, inv(16)
M5: Acute monocytic leukemia
M6: acute erythroleukemia
M7: acute megakaryocytic leukemia
352
AML M3: acute promyelocytic leukemia
- DIC, at presentation of during treatment with ATRA
- characteristic translocation t(15;17) PML-RAR fusion gene that codes for abnl retinoic acid receptor
- Treatments with all-trans-retinoic acid helps in maturation of the arrested promyelocytic cells
353
What has plenty of granules are Auer rods?
- Faggot cells (Auer rods)
- promyelocytes with granules
354
When do you commonly see gum infiltration?
- AML-M5
355
When do you commonly see DIC?
AML-M3
356
Morphology of AML
- blasts or promyelocytes > 20% bone marrow cellularity
- myeloblasts: delicate chromatin, 3-5 nucleoli, fine azurophilic cytoplasmic granules
- Auer rods
- Monoblasts, erythroblasts, or megakaryoblasts are also possible
357
Auer rods
- red-staining, rod-like structures fused azurophil granules
- Seen in myeloblasts (M2 and M3 of AML)
- not present in myeloblasts in CML
- particularly numerous in acute promyelocytic leukemia
358
Myelodysplastic syndromes
- bone marrow replacement by clonal proliferation of multipotent stem cell that can differentiate into RBC/WBC/platelets in an ineffective and disordered manner
- peripheral blood shows cytopenias
- Further stem cell mutations transform into AML
- t-MDS : idiopathic, some after chemo/radiotherapy
359
Pathogenesis of myelodysplastic syndromes
- clonal abnormalities
- monosomy 5/7, with deletions of 5q, 7q, and trisomy 8
- 5q syndrome
360
5q syndrome
- more common in women
- severe anemia
- preserved or elevated platelet counts
- often responds to treatment with analogs of thalidomide
361
Peripheral smear of myelodysplastic syndromes
- Severe pancytopenia
- normocytic to macrocytic
- dimorphic RBCs with a high RDW
- leukoerythroblastosis
362
Bone marrow findings of myelodysplastic syndromes
- megaloblastoid erythroid precursors, RINGED SIDEROBLASTS
- WBC precursors with abnormal granules/nuclear maturation
- megakaryocytes with single nuclear lobe or multiple separate nuclei
- myeloblasts <20% of granulocytes (If many myeloblasts, think AML)
363
Clinical features of myelodysplastic syndromes
- 50-70 years of age
- infections, anemia symptoms, hemorrhages
-response to conventional chemo is poor
- transformation to AML occurs in 10-40%
- prognosis is variable
