Flashcards in Hematologic Malignancies III Deck (73):
What are "acute leukemias"?
Cancer caused by proliferating bone marrow cells that resemble undifferentiated progenitors (“blasts”)
What is the prognosis for acute leukemias?
What is the major defining criteria for diagnosis of an acute leukemia?
more than 20% blasts in marrow or peripheral blood
or less than 20% blasts with positive cytogenetics
T or F. Using ontogeny (understanding the origin cell from which a cancer arise) has very little clinical utility in leukemia diagnosis
What is an essential part of diagnosing any acute leukemia?
How does immunophenotyping help diagnose acute leukemia?
In particular, it is used to distinguish between those of myeloid lineage (acute myeloblastic leukemia, AML) and those of lymphocyte lineage (acute lymphoblastic leukemia, ALL).
What markers are found on blasts?
What markers are found on myeloid blasts?
What markers are found on lymphoid blasts?
TdT+ (B and T lymphoid blasts),
CD10 (CD10 is a marker of immature B-cells, usually in between the blast and mature B-cell stages.)
What markers are found on B-lymphocytes/blasts/lymphoma?
What markers are found on T-lymphocytes/blasts/lymphoma?
What is the major problem with immunophenotyping?
many leukemias (and other hematologic malignancies) break the rules – their immunophenotype appears to be mixed.
So immunophenotype BY ITSELF did not provide us with a very good diagnostic system, although it is an essential PART of our current diagnostic workup.
What is more clinically useful criterion used for acute leukemia diagnosis?
What are the five genotypes common in AML subtype leukemias?
1) t(15;17)(q22;q12) PML-RARa + IFKZ1 mutation (+)
2) t(8;21)(q22;q22) RUNXT1-RUNX1
3) inv(16) CBFb: MYH11
What is a genotype common in ALL subtype leukemias?
t(12;21)(p13;q22) TEL-AML1 (ETV-6-RUNX1)
Again, what is the MAJOR criteria for diagnosing an acute leukemia?
If blasts make up more than 20% of the cells in the bone marrow or peripheral blood, the diagnosis is acute leukemia.
What is the problem with the diagnostic key to diagnosing acute leukemias being a number of blasts as it is?
Every patient with a bone marrow blast (or peripheral blood) count of >20% must have been at some point less than 20% (this is called a MPD)
If you suspect acute leukemia BUT BM/PB blasts are not elevated above 20%, whats your next step?
cytogenetics indicating acute leukemia (if not positive, other diagnosis)
after the diagnosis of acute leukemia is confirmed, sub typing is required
How is sub typing of acute leukemias performed?
may also required FISH or sequence-based studies
Note that there are 14 current subtypes of AML. What are the major three?
How are the three major subtypes of AML diagnosed?
by (cyto)genetics alone REGARDLESS of blast count
AML with t(15;17) used to be aka?
previously called AML-M3, or acute promyelocytic leukemia, or APL
What does the t(15,17) result in?
fusion of a transcription factor (RAR-alpha, or RARA) to PML which is involved in organizing a number of nuclear structures into spatially-defined subdomains.
Review: When activated by the signaling molecule retinoic acid (RA; it’s just vitamin A), RARA normally activates transcription of a series of genes involved in the DIFFERENTIATION of myeloid precursors into neutrophils. The fusion protein (PML-RARA) blocks that process, probably by binding the target gene promoters and NOT activating transcription.
So what is the end result of AML with PML-RARa fusion?
- dominant negative block of normal RARa function
- inhibited granulocyte differentiation
AML with t(15;17)(q22;q12); PML-RARA accounts for what percentage of AMLs?
What was the original hypothesis about how to treated this AML?
it suggested that we might be able to nudge it into acting normally – i.e. inducing differentiation – with high doses of RA, and in particular with an active enantiomer of RA, “all trans retinoic acid” or ATRA.
AND at the time this hypothesis came up (in the 1980’s), ATRA was clinically available as an old standard topical treatment for acne. So they tried it (intravenously), AND IT WORKED!!!
So what does infusion of ATRA in t(15,17) AML patients result in?
ATRA induces differentiation of the blasts to granulocytes and CLINICAL REMISSION
How does ATRA work?
the fusion protein has multiple functions, and ATRA actually destabilizes it (as does another drug now used with ATRA for this condition, arsenic trioxide).
What is seen in a BM smear in t(15,17) AML?
blasts packed with auer rods
What are Auer rods?
needle shaped red crystals seen in the cytoplasm of some myeloid leukemias
They are NEVER seen in reactive conditions
What is the immunophenotype for t(15,17) AML?
weak/absent CD34, HLA-DR,
CD13+, and CD33+
Clinical presentations of this AML? Patient population?
- severe thrombocytopenia
- either leukocytosis or leukopenia
- at any age
What is AML with t(8;21)(q22;a22) caused by?
Runx1-Runx1T1 fusion of the two transcription factors resulting in dominant negative repression of myeloid maturation
What is Runx1?
part of a heterodimeric transcription factor called Core binding factor (CBF)
What age does AML with t(8;21)(q22;a22) present?
What is the immunophenotype of AML with t(8;21)(q22;a22)?
CD34+, HLA-DR+, CD13+, CD33 weak
Prognosis for AML with t(8;21)(q22;a22)?
good response to chemo
What is AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); caused by?
fusion proteins of a transcription factor with MYH1 resulting in dominant negative repression of myeloid maturation
5-8% of AML cases
What is CBF-beta?
the other component of the CBF heterodimer
When does AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); present? Prognosis?
kids- good prognosis
What is the immunophenotype of AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22);?
CD34+, CD117+ (blasts)
CD13+, CD33+ (granulocytes)
CD14+, CD11b+ (monocytes)
The three well-characterized AML types with a relatively good prognosis only make up 15-20% of cases. What makes up an additional 50% of cases?
AMLs with normal cytogenetics make up almost half of cases, and they can trend toward any morphologic type (granulocytes, monocytes, red cell precursors, megakaryocytes).
What is an important point about AMLs with normal cytogenetics?
HOW THEY ARE TREATED DEPENDS ON THE RESULTS OF TARGETED DNA SEQUENCING STUDIES
so, if a patient is diagnosed with AML, their cytogenetic findings are normal, and no molecular studies have been done, the study was not done properly.
AMLs with a complex karyotype represent what % of AMLs?
5-10%- poor prognosis
What constitutes "complex" karyotype in AMLs?
AML cases with three or more cytogenetic findings (such as translocations, trisomies, or monosomies) are currently grouped into this poor-prognosis category (such as those labeled as “high cytogenetic risk”).
What else do complex karyotype AMLs typically show?
deletions or other mutations affecting TP53.
Immunophenotype of complex karyotype AMLs and those with normal cytogenetics?
blast markers (CD34, CD117)+, typically CD33+
What age group is mostly affected by ALL?
It is primarily a pediatric disease (3-7 yr old primary and a small resurgence at 40+); 75% of cases occur in kids, and over 80% of acute leukemias in kids are ALL.
In kids, it can usually be cured (over 80% of the time). In adults the cure rate is lower (~50%).
What do the blasts in ALL look like?
the blasts in this condition show few distinguishing characteristics.
They are just large, monotonous cells with big nuclei, prominent nucleoli, little cytoplasm, and no cytoplasmic granules.
As noted previously, the lineage of cells with this appearance has to be determined by immunophenotyping (usually flow cytometry).
But prognosis and choice of therapy in ALL depends on further characterizing them via ____.
And there are a very large number of genetic subtypes. About 2/3 of these genetic subtypes can be identified by cytogenetic studies; the rest require FISH or sequencing studies.
What are some major types of ALL? 4
1) t(9;22)(q34;q11.2); BCR-ABL1 (bad prognosis)
2) t(v;11q23); MLL rearranged (bad prognosis)
3) t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) (good prognosis)
4) Hyperdiploid (>50 chromosomes) (good prognosis)
remember, there are others
ALL ALLs require what for diagnosis? Prognosis?
25+% marrow blasts
prognosis- good, 90% cure rate
presents in kids (25% of all pediatric B-ALL)
What does ALL with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) result in?
fusion protein that acts as a dominant negative transcription factor with multiple effects on gene expression that in general block maturation
Immunophenotype of ALL with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)?
TdT+, CD34+, CD10+
What is TdT?
TdT is terminal deoxynucleotide transferase, and it’s responsible for the addition of extra nucleotides to the variable regions of immunoglobulins, and the Ig-like T-cell receptors, at a very early point in the differentiation of both cell types.
TdT is exactly what you’d expect to find in a clone of cells stuck at an early stage in B-cell or T-cell differentiation.
What does ALL with t(9;22)(q34;q11.2); BCR-ABL1
fusion protein of part of a serine-threonine kinase (BCR) to a tyrosine kinase (ABL1) which results in increased PROLIFERATION
NOTE: (Usually “p190”, a different size than the “p210” seen in CML).
Patient population of ALL with t(9;22)(q34;q11.2); BCR-ABL1?
older adults (25% of ALL cases) and kids less than 1 y/o (2-4% of pediatric ALL)
Immunophenotype of ALL with t(9;22)(q34;q11.2); BCR-ABL1?
CD10+, CD19+, TdT+
Prognosis of ALL with t(9;22)(q34;q11.2); BCR-ABL1?
What is another mutation seen in most (84%) of ALL with t(9;22)(q34;q11.2); BCR-ABL1 cases?
IKZF1 transcription factor- inhibits DIFFERENTIATION
Most 9;22 cases have taken two particular genetic hits, one that blocks maturation and another that enhances proliferation.
What does ALL with t(v;11q23) result in?
fusion of a transcription regulator (histone methyl transferase) to any of several partners resulting in inhibition of DIFFERENTIATION (Also found in AML)
What else is common in ALL with t(v;11q23)?
FLT3 mutation (in 20% of cases) which enhances PROLIFERATION
Clinical presentation of ALL with t(v;11q23)?
most common leukemia in kids less than 1 y/o
Immunophenotype of ALL with t(v;11q23)?
CD10-, CD19+, TdT+
Prognosis of ALL with t(v;11q23)?
T or F. T-cell ALL’s lack expression of the B-cell markers we’ve covered (CD20, CD10), and B-cell ALL’s lack CD3 and CD5 expression.
What do both T-ALLs and B-ALLs express?
What is the result of T-ALL?
most have a translocation of an oncogene to a T-ecll receptor promoter (Any of the three TCR loci in the genome)
could be with multiple partners
What is a common motif for lymphoid malignancies?
oncogene translocation to an Ig of TCR promoter
Clinical presentation of T-ALL?
kids. 25% of pediatric B-ALL. Often with thymic mass or lymph node, spleen involvement.
Immunophenotype of T-ALL?
TdT+, CD3+, CD5+; can express myeloid or B-cell antigens as well
Prognosis of T-ALL?
High risk- requires an intensive chemo regimen (that improves survival to that comparable to kids with B-ALL)
This is called "risk stratification"