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226 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 227

TABLE 16–3. Common somatic mutations encountered in the major myeloid malignancies. (Continued)
Functional class of Nature of mutation and Approximate Prognostic and/or therapeutic
Gene encoded protein functional consequence incidence implications, if any
TP53 Master regulator of cell 17p deletions and inacti- TP53 mutations seen Extremely poor prognosis; MDM2
cycle, DNA damage vating point mutations; in only 9% of older (negative regulator of TP53)
response and apoptosis MDM2 overexpression; patients with de novo antagonists in clinical trials; mutu-
(tumor suppressor) other mechanisms of loss AML, but much more ally exclusive of FLT3 and NPM1
of function common in second- mutations
ary and t-AML
PHF6 X-linked tumor suppressor Loss of function 3% Mutations confer poor prognosis
mutations
NRAS Survival signaling molecule “Class I” mutations that 13% of CN AML; RAS RAS mutations predict for benefit
confer survival and prolif- mutated in 19% of of post remission HiDAC
eration advantages elderly patients with
AML
WT1 Transcription factor that Loss of function 10%; most frequent in Unclear effect on prognosis; likely
may act both as a tumor mutations CN AML negative impact
suppressor gene and an
oncogene
KIT Tyrosine kinase (signaling Activating mutations 30-40% of CBF AML Mutated c-KIT confers adverse
molecule) prognosis in CBF AML; ?role
of TKIs
MYELODYSPLASTIC SYDROMES (MDS)
SF3B1 RNA splicing protein – core Spliceosome 24% Extremely strong correlation with
component of U2 snRNP, mutations→decreased or ringed sideroblasts; indolent
which recognizes the 3’ increased transcription of course with prolonged survival
splice site at intron-exon normal pre-mRNA, exon (RARS); acquisition of JAK2 V617F
junctions skipping, intron retention causes RARS-T
and cryptic splice sites;
SF3B1 mutations lead
to abnormal splicing of
ABCB7
TET2 Catalyzes alpha-ketog- Loss of function 20-22% Predict response to HMAs, but
lutarate-dependent mutations→ increased overall confer poor prognosis,
conversion of 5-methylcy- promoter methyla- even after HSCT
tosine to 5-hydroxymeth- tion→increased self-
ylcytosine, leading to DNA renewal and impaired
demethylation differentiation
SRSF2 RNA splicing protein Spliceosome muta- 14% Co-occurrence of TET2 and SRSF2
tions→decreased or mutations highly specific for
increased transcription of CMML; mutually exclusive with
normal pre-mRNA, exon SF3B1 mutation; progression from
skipping, intron retention SRSF2- mutated RCMD-RS to RAEB
and cryptic splice sites may involve appearance of STAG2
mutations
ASXL1 Member of polycomb fam- Loss of function muta- 10%; >40% of Poor prognosis
ily of chromatin binding tions in C-terminal gener- patients with CMML
proteins; epigenetic modi- ate a dominant-negative
fier; functions as ligand-de- protein that inhibits its
pendent coactivator of wild type counterpart and
retinoic acid receptor other members of poly-
comb protein complex
DNMT3A DNA methyl transferase Loss of function muta- 10-15% Poor prognosis, even after HSCT
tions causing reduced
methylation in mutant
genomes
(continued)

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