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228 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 229

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
MPL Thrombopoietin receptor Activating mutations, e.g., 5-10% of cases of ET MPL W515L activates JAK-STAT sig-
W515L or MF naling; associated with older age,
female sex, lower Hgb level and
higher platelet count
CBL TK-associated ubiquitin Mutants encode a dom- 6% of cases of MF Enhanced JAK-STAT signaling
ligase that negatively inant negative protein
regulates signal transduc- that inhibits the ubiquitin
tion by targeting receptor ligase activity of the wild
TKs for degradation (tumor type protein and of its
suppressor) homolog, CBLB (inactivat-
ing mutations)
LNK Membrane-bound adaptor Inactivating mutations Rare cases of JAK2 Enhanced JAK-STAT signaling
protein that inhibits wild V617F-negative ET or
type and mutant JAK2 MF; more common
signaling in blast phase of MF
(13%)
CALR Endoplasmic reticulum Frameshift mutations in Absent in PV; pres- Predicts for more indolent clinical
chaperone (calreticulin) exon 9 create mutant ent in most (~73%) course than JAK2 V617F; patients
protein with novel C- patients with ET or MF have lower Hgb levels and higher
terminal→altered without JAK2 or MPL platelet counts; mutant CALR
subcellular localiza- mutations (helps dis- activates JAK-STAT signaling in
tion and impaired Ca tinguish clonal MPNs myeloid cells
2+
binding from reactive causes
of thrombocytosis)
TET2 Catalyzes alpha- Loss of function 16% in PV, 5% in ET, No effect on survival, leukemic
ketoglutarate- mutations→ 17% in MF; 14% in transformation or thrombosis; may
dependent conversion increased promoter post-PV or post-ET correlate with anemia in MF
of 5-methylcytosine to methylation→increased MF; incidence
5-hydroxymethylcytosine, self-renewal and impaired increases with age
leading to DNA demethy- differentiation
lation
ASXL1 Member of polycomb Loss of function muta- 8% of patients with
family of chromatin binding tions in C-terminal gener- MPNs
proteins; epigenetic modi- ate a dominant-negative
fier; functions as ligand- protein that inhibits its
dependent coactivator of wild type counterpart and
retinoic acid receptor other members of poly-
combprotein complex
IDH1/2 Krebs cycle enzymes IDH mutants produce <5% of cases of MF
2-hydroxyglutarate (much higher (~22%)
from alpha-ketogluta- in blast phase); 1-2%
rate, which inhibits TET of cases of ET and PV
enzymes, causing DNA
hypermethylation
EZH2 Tumor suppressor-histone Loss of function 13% in MF; 12% in Independently associated with
methyltransferase (cata- mutations→loss of PRC2 MDS/MPN overlap shorter survival in patients with
lytic subunit of polycomb activity→increase in syndromes MF
repressive complex, PRC2) hematopoietic stem cell
number and activity
DNMT3A DNA methyl transferase Loss of function muta- 7-10%
tions causing reduced
methylation in mutant
genomes
IKZF1 Transcription factor Generally deletions Rare in chronic phase Important step in leukemic
(del7p) rather than muta- MPNs, but 19% in transformation
tions; late events blast phase
(continued)

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