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1350 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1351

lymphoid malignancies. Mouse models of Dnmt3a loss demonstrate for methylating lysine 27 on histone 3 (H3K27). The H3K27 methyl
hematopoietic stem cell exapansion with impaired differentiation. Dys- mark is associated with closed chromatic and reduced expression of
plasia and leukemic transformation do not occur in this mouse model, neighboring genes. Loss-of-function mutations in EZH2, present in 6
suggesting that DNMT3A loss is sufficient to provide a stem cell growth percent of MDS, are associated with a poor prognosis in a manner that
advantage, but insufficient to cause an MDS or AML disease phenotype. is independent of common prognostic scoring systems. 100,102,134 This is
This is consistent with the finding that somatic DNMT3A mutations can largely because EZH2 mutations are not strongly associated with adverse
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be found in persons without cytopenias or other elements of disease. clinical features such as increased proportions of blasts, complex karyo-
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Therefore, cooperating mutations or microenvironmental changes are types, or severe cytopenias. Other members of the PRC2, EED and
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likely necessary determinants of disease. Mutations of DNMT3A are SUZ12, can also be mutated in very rare cases of MDS. Loss of PRC2
found most often in patients with normal karyotypes and cooccur with activity may, in part, promote the development and progression of MDS
SF3B1 mutations more often than expected by chance. 90,153 DNMT3A through derepression of HOX genes, which are often upregulated or
mutations in MDS patients appear to confer a poor prognosis. 150,154 aberrantly expressed in self-renewing leukemic cells. 176
TET2 The second member of the ten-eleven translocation gene ASXL1 ASXL1 is a frequently mutated MDS gene believed to be an
family, TET2, is among the most frequently mutated MDS genes pres- epigenetic “reader” capable of binding to specific histone marks through
ent in 20 to 30 percent of cases, and in more than 40 percent of patients its highly conserved PHD domain. Mutations of ASXL1, present in
with CMML. It encodes a methylcytosine oxygenase that converts 5- 20 percent of MDS and 40 percent of CMML, are largely heterozygous
methylcytosine (5-mC) in to 5-hydroxymethylcytosine (5-hmC) using truncating mutations in its terminal exon. These lesions are associated
iron and α-ketoglutarate (αKG) as cofactors. The TET2 enzyme can with a poorer prognosis than predicted by common clinical assessments
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further oxidize 5-hmC into 5-formyl- and 5-carobxycytosine (5-fC and alone. 134,177,178 ASXL1 interacts directly with the PRC2, directing the
5-caC, respectively). This may represent a mechanism for the active activity of EZH2 to specific genomic regions. Loss of ASXL1 is asso-
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demethylation of cytosines as 5-caC can be decarboxylated to form ciated with absent H3K27 trimethylation at the HOXA gene cluster.
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cytosine or treated as a mismatched nucleotide by the base excision ASXL1 mutations may cooperate with mutations in various other genes
DNA repair pathway. Mutations in TET2 are typically truncating or such as SRSF2, U2AF1, TET2, and NRAS, as mutations of these genes
clustered in regions that encode catalytic domains indicating an asso- cooccur more often than predicted by chance alone. In patients with
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ciated loss of function. Mutations are often compound heterozygous or germline mutations of the transcription factor GATA2, somatic ASXL1
in areas of aUPD on chromosome 4q, resulting in no viable wild-type mutation appears to be a common concurrent event at the time of MDS
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allele. Patients with TET2 mutations demonstrate increased global or AML development. 180,181
DNA methylation, lower levels of 5-hmC and are more likely to have an Mutated Transcription Factor Genes Mutations of hematopoi-
elevated monocyte count. 158,159 Mouse models of Tet2 loss show a similar etic transcription factors in MDS are typically somatic events, but can
phenotype with increased stem cell and progenitor numbers, impaired be present in the germline either as inherited or spontaneous congenital
differentiation, and myeloid skewing of hematopoiesis. 160–163 As with events in rare cases. RUNX1 is the most frequently mutated transcrip-
DNMT3A, TET2 mutations can also be found in various myeloid and tion factor in MDS. This gene, previously known as AML1, encodes the
lymphoid malignancies, as well as in persons with clonal hematopoiesis alpha core binding transcription factor subunit and is altered in many
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and no hematologic disesase. Clinically, TET2 mutations are not likely myeloid and lymphoid malignancies. In the acute leukemias, RUNX1
drivers of MDS prognosis and have variably been associated with favor- is a frequent translocation partner with other genes such as RUNX1T1
able, neutral, or poor outcomes. 134,164,165 (previously known as ETO) as part of t(8;21) in AML and with ETV6
IDH1 and IDH2 Only mutations in the isocitrate dehydrogenase in (previously known as TEL) as part of t(12;21) in acute lymphocytic
genes 1 and 2 (IDH1 and IDH2, respectively) are exclusive of TET2 leukemia (ALL). RUNX1 is mutated in 10 to 15 percent of MDS where it
mutations, suggesting that they share a common pathogenic mecha- is associated with a poor prognosis, increased rates of leukemic progres-
nism. Mutations of these IDH genes are common in AML and gliomas, sion, and thrombocytopenia. 134,135 Mutations can affect one or both alle-
but relatively rare in MDS, comprising approximately 5 percent of cases. les and often involve the DNA-binding RUNT domain or truncate the
Oncogenic IDH mutations are always heterozygous missense mutations more distal protein interaction domain. 182–184 Persons with congenital
of specific codons that result in an important change of enzyme func- mutations of RUNX1 can have an autosomal dominant FPD-AML char-
tion. Instead of converting isocitrate to αKG while generating an nicoti- acterized by numerical and functional platelet abnormalities that pre-
namide adenine dinucleotide phosphate (NADPH) from nicotinamide cede transformation to AML by many years. Penetrance of FPD-AML is
adenine dinucleotide phosphate–positive (NADP ), the mutant forms variable and the long latency to transform indicates the need to acquire
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of IDH1 and IDH2 catalyze the conversion of αKG to 2-hydroxygluta- cooperating mutations. 43,185,186 Mutations of C/EBPA can also cause
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rate (2-HG) while oxidizing NADPH to NADP . The 2-HG produced familial propensity for AML in an autosomal dominant fashion, but are
is considered an oncometabolite, which can interfere with the activity very rare mutations in MDS as somatic or inherited abnormalities. 187
of αKG-dependent oxygenases, including the TET family of genes, ETV6 The ets-like transcription factor 6, ETV6, is frequently rear-
prolyl hydroxylases, collagen synthesis enzymes, and various histone ranged, deleted, or mutated in hematologic malignancies. In MDS,
demethylases. 167–171 Mouse models of leukemic IDH mutations in the ETV6 mutations are present in approximately 5 percent of cases, where
hematopoietic system share several features with Tet2-null mice, includ- they are independently associated with shorter overall survival and pro-
ing global DNA hypermethylation and increased proportions of early gressive disease. 134,188
progenitor cells. In MDS, the clinical significance of IDH mutations GATA2 Germline GATA2 mutations are responsible for several
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is mixed and may depend on the nature of the mutation. Inhibitors of different congenital syndromes with overlapping features including
the neomorphic activity of mutant IDH enzymes represent promising a predisposition to marrow failure, MDS, and AML. 53,58,189,190 Familial
therapies as the effects of 2-HG exposure appear to be reversible. 174 GATA2 mutations can manifest as the monoMAC syndrome, charac-
EZH2 and Other Rare Mutations Several regulators of histone terized by monocytopenia and mycobacterial infections; Emberger
modifications are recurrently mutated in MDS and MDS/MPN disor- syndrome, characterized by congenital lymphedema and risk of devel-
ders. These include the histone methylase EZH2, which encodes the cat- oping MDS; or as a deficiency in monocytes, B and natural killer (NK)
alytic subunit of the protein-repressive complex 2 (PRC2) responsible lymphocytes, and dendritic cells. Patients can also have sensorineural
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