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