CML Module Flashcards
1
Q
Chronic Myeloproliferative Disorders: Definition
A
Malignant proliferation of myeloid cells (NOT blasts, but maturing cells) in blood and bone marrow
2
Q
The 4 myeloproliferative disorders
A
Chronic Myeloid Leukemia (CML)
Polycythemia Vera (PV)
Essential Thrombocythemia (ET)
Myelofibrosis (MF)
3
Q
What is proliferating in CML?
A
Neutrophils
4
Q
What is proliferating in PV?
A
Red cells
5
Q
What is proliferating in ET?
A
platelets
6
Q
What is proliferating in MF?
A
Everything
7
Q
Features of myeloproliferative disorders (general)
A
Adults Long clinical course Increased WBC with left shift Hypercellular marrow Big spleen Mutated Tyrosine kinases
8
Q
What can myeloproliferative disorders develop into?
A
Acute leukemia
9
Q
Chronic Myeloid Leukemia
A
Neutrophilic leukocytosis
Basophilia
Philadelphia Chromosome
Three phases
10
Q
Lab Findings of CML
A
Increased WBC Neutrophilia with Left Shift Basophilia Decreased Hgb Increased platelets Decreased LAP
11
Q
LAP
A
enzyme in neutrophils.
In benign process - high.
Malignant - low.
12
Q
Philadelphia Chromosome
A
Chunk of 9 breaks off - adds to 22.
22 is the Philadelphia chromosome
Makes active TYK
13
Q
Symptoms of CML
A
Slow onset
Fever, fatigue, night sweats
abdominal fullness (splenomegaly)
14
Q
Signs of CML
A
Big spleen and big liver
15
Q
3 phases of CML
A
Chronic, accelerated, blast crisis
16
Q
Chronic CML
A
Stable counts, controlled
17
Q
Accelerated CML
A
50% from chronic.
Unstable. Blast crisis in 6-12 months
18
Q
Blast Crisis
A
50% for chronic.
Acute leukemia of either lineage.
High mortality
19
Q
Remission of CML
A
Best detected by PCR. No BCR-ABL1
20
Q
About Polycythemia Vera
A
High RBCs (makes blood sludgy)
Different from secondary polycythemia (altitude)
Thrombosis and hemorrhage
JAK2 mutation
21
Q
Polycythemia mean…
A
increased red cell mass
22
Q
Primary polycythemia
A
intrinsic myeloid cell problem
23
Q
secondary polycythemia
A
increased EPO
24
Q
Clinical signs of PV
A
headache, pruritis, dizziness
Thrombosis, infarctions
25
Symptoms of PV
big spleen and liver. Flushing.
26
JAK2 Pathway
Unique pathway that does not involve secondary messengers. Brings growth factors to nucleus and stimulates division.
27
JAK STAT in PV
Mutated JAK2
| Inhibitory portion does not work - continually signaling
28
Treatment of PV
phlebotomy
| Maybe myelosuppressive drugs
29
Prognosis
Median survival 9-14 years
Death from thrombosis or hemorrhage
Leukemic transformation in some patients
30
About Essential Thrombocythemia
Very high platelet count
Young women
Diagnosis of exclusion
Thrombosis and hemorrhage
31
Diagnostic criteria for ET (platelet)
Platelet count > 600,000
32
Diagnostic criteria for ET (Hgb)
>13 or RBC mass normal
33
Diagnostic criteria for ET
Platelets count >600,000
RBC mass normal or Hgb >13
No Philadelphia chromosome or marrow fibrosis
34
Signs and Symptoms of ET
Bleeding, thrombosis (even though lots of platelets - they aren't working)
Purpura, bruising, pallor, tachycardia, big spleen
35
Treatment of ET
platelet pheresis
Maybe myelosuppressive drugs
Aspirin
36
Prognosis of ET
5-8 years
Death from thrombosis or hemorrhage
Leukemic transformation
37
Chronic Myelofibrosis course
panmyelosis --- then marrow fibrosis
| Extramedullary hematopoiesis
38
Hallmark of Myelofibrosis (Smear)
Teardrop red cells
39
Signs and Symptoms of MF
LUQ fullness, weakness, fatigue, palpitations
| Splenomegaly, pallor, tachy
40
Treatment of MF
Supportive
| Maybe myelosuppressive drugs
41
Prognosis of MF
3-5 years
Death from marrow failure
Leukemic transformation possible
42
Why is the SH3 domain important?
It is a common motif to establish multi enzyme complexes
43
BCR-ABL1 mimics what?
Growth factor activation
44
Mechanism of Imatinib
ATP binding site competitive inhibitor
45
SE of Imatinib
```
muscle cramps
asthenia (wasting syndrome)
edema
skin fragility
diarrhea
tendon and ligament abnormalities
```
46
Why does Imatinib have broad SE?
TYK have many families. May work on many different 'branches'
47
What is so special about Imatinib?
It is a small molecule drug that binds at the ATP binding site for kinase activity, rather than selectively inhibiting the BCR-ABL1 protein.
Has less collateral damage than one would think
48
What enzyme metabolizes Imatinib
CYP3A4 (grapefruit juice = bad)
49
Resistance to Imatinib
Altered metabolism CYP3A4
Altered membrane transport
Loss of p53 (which confers resistance to apoptosis)
Over expression of BCR-ABL1
Point mutations, especially in binding domain
50
Biggest mutation in CML
T313I
51
What happens in T315I mutation
Loss of binding parter, big thumb sticks out of binding pocket.
Imatinib can no longer keep from phosphorylating and cell signaling will continue as a result.
52
How common is T315I?
30% of cancers resistant to Imatinib have this mutation.
53
Nilotinib
Induces deeper and faster remissions
| lower levels of BCR-ABL transcripts
54
Side effects of Nilotinib?
Same as Imatinib
55
How does Nilotinib work?
Has a hydrophobic binding pocket with fluorine group
56
Does Nilotinib work with T315I resistance?
No
57
Dasatinib
Works against BCL-ABL1 and Src
| Active against point mutations, except T315I
58
SE of Dasatinib
fluid retention and pulmonary HTN
| Inhibits some threonine and serine kinases (DIRTY)
59
Bosutinib
Active against BCR-ABL1 and Src
| Works on most point mutations, except T315I
60
Ponitinib
Designed based on T315I
| Active against this mutation
61
SE of Ponitinib
Causes clots and arterial fibrosis that can be fatal
62
Treatment of CML is an example of...
successful molecular medicine
63
Initiating event of CML?
Translocation at (9;22)
64
What happens with t(9:22)
Genomic translocation creates new gene encoding for an active tyrosine kinase
65
What differentiation pathway does CML affect?
Neutrophil
66
Neutrophils arise from...
hematopoietic stem cells --> then Multipotential progenitor and Common myeloid progenitor
67
3 stages of Neutrophil development
Stem cell - undergoes self renewal and proliferation
Progenitor - just proliferation
Committed - neither - one fate
68
Self renewal and proliferation are tightly regulated by..
extracellular signaling from marrow. Immune system.
| ensures that appropriate number of neutrophils are produced.
69
BCR-ABL1 is a....
constitutively active tyrosine kinase - activates proliferation and blocks apoptosis in the absence of extracellular signals.
70
Where does the BCR-ABL1 mutation arise?
Hematopoietic stem cell
| Passed down to all progeny
71
Expression of BCR-ABL1 fusion protein disrupts....
normal neutrophil differentiation
72
BCR-ABL and selective advantage?
Progenitor cells proliferate more and survive longer
| Acquire more mutations to become oncogenic
73
Do constitutively active BCR-ABL1 cells self renew?
NO.. still mature
74
How does CML develop into the accelerated/blast phase?
GMP acquires ability to self renew. Blocks differentiation. Results in huge expansion on immature cells
75
What does b-catenin do?
transcription factor activated by WNT extracellular ligand
| Self renewal of stem cells
76
Mutation in b-catenin leads to...
Blast crisis
77
What happens in the translocation event?
Genomic DNA is physically rearranged between 9 and 22
78
Which one is the philadelphia chromosome (9 or 22)
22 (22q-)
79
Mechanism for translocation?
non-homologous end joining
| p210 or p190
80
Normal role of BCR
inhibition of inflammatory response
81
Normal role of ABL1
Kinase used for DNA repair, cytoskeletal organization
82
what normally regulates ABL1 activity
myristate, a long chain FA
83
ABL is mainly located _____, BCR-ABL is _______
nuclear, cytoplasmic
84
the ______ domain of BCR promotes dimerization
coil-coil
85
_____ attachment is lost from ABL1 in mutation
myristate
86
Tyrosine 177
BCR phosphorylation creates new binding site on Y177 (in mutated protein)
87
Signaling in normal ABL
myristate blocks, then extracellular signaling, opens conformation, dimerization occurs allowing transphosporylation
Phos TK are the platforms for signaling
88
Signaling in BCR-ABL1
No myristate so open (no signaling needed), coil coil of BCR promotes dimerization.
89
Why is Y177 only subject to phosphorylation in mutation?
BCR isn't a tyrosine kinase normally
90
Why does the inactivation of BCR-ABL result in apoptosis?
Mutant cells depend on the pathway
91
Why must imatinib be taken for life?
Doesn't work against stem cells. If stop, quiescent stem cells will restart the disease
