LWBK1006-31 LWW-Govindan-Review December 12, 2011 19:43
Chapter 31•Acute Leukemias 443ANSWERS
Answer 31.1. The answer is D.
The favorable t(8;21) translocation results in the juxtaposition of the ini-
tially named AML1 gene with the ETO gene (the AML gene and the
eight-twenty-one gene). These two have recently been renamed RUNX1
and RUNX1T1, respectively. RUNX1 is a member of the core-binding
factor family of transcription factors, which regulate differentiation of
normal blasts. This fusion protein creates a dominant negative protein,
which results in a differentiation block. Inv(16) and thet(16;16) rear-
rangements likewise result in dominant negative effects on core-binding
factors and are associated with a favorable prognosis.Answer 31.2. The answer is A.
The DNMT3A gene encodes the DNA (cytosine-5)-methyltransferase 3A
enzyme that catalyzes the addition of a methyl group to the cytosine
residue of CpG dinucleotides. In patients with AML with normal cyto-
genetics, the presence of DNMT3A mutations is independently associ-
ated with poor outcomes. CEBP/is a transcription factor involved in
myeloid differentiation thought to be activated by ATRA treatment in
APL. Mutations in the CEBPA gene have been noted in other FAB-AML
classifications and have been associated with a superior outcome com-
pared with the wild-type transcript. NPM mutations, in the absence of
the FLT3-ITD, have also been associated with improved prognosis. Age
is a strong prognostic factor. However, it is patients who are older than
65 years who have a worse prognosis. Her young age would be a marker
of a good prognosis.Answer 31.3. The answer is A.
Cytopathology requires greater than 5% blasts on a bone marrow biopsy
to diagnose AML relapse. This results in a sensitivity of 1 in 20. A cyto-
genetic review of 30 metaphases results in a 1 in 30 sensitivity. FISH has a
sensitivity of approximately 1 in 500. PCR techniques allow sensitivity of
approximately 1 in 10^4. However, both FISH and PCR require screening
for defined cytogenetic changes. Because initial cytogenetic changes typi-
cally recur during AML relapse, this is generally not a significant barrier,
unless patients present with uncommon cytogenetic changes for which
FISH and PCR probes are not commercially available.Answer 31.4. The answer is C.
Current models of leukemia suggest that two separate classes of mutations
are required for leukemogenesis: an activating mutation and a differen-
tiation mutation. Activating mutations result in dysregulation of prolif-
erative signaling pathways and thus lead to hyperproliferation. Impor-
tant targets of activating mutations in leukemia include FLT3-ITD, RAS,
BCR-ABL, TEL-PDGFR, and PTPN11. Many of these contain tyro-
sine kinase domains. Leukemogenic mutations often result in constitu-
tive kinase activity and thus constitutive activity in signal transduction