Page 1067 - Hematology_ Basic Principles and Practice ( PDFDrive )

950 Part VII Hematologic Malignancies

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DNMT3A mutations have recently been shown to exist with modest deleterious cytogenetic occurrence in MDS, though not all 7q
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frequency in healthy older adults and are in fact significantly more deletions affect the EZH2 locus. Mutations in EZH2 itself are
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common than mutations in any other single gene, with an overall found in 5% to 10% of patients with MDS and 20% to 30% of
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frequency that is significantly higher than their aggregate representa- patients with CMML. Consistent with the model of EZH2 as a
tion among hematologic malignancies. This discrepancy could either negative regulator of pluripotency and survival, mutations tend either
reflect the same long latency of DNMT3A-mutated hematologic to be inactivating frameshift or nonsense mutations, or missense
malignancy that was observed in mouse models, or it could suggest mutations concentrated in the gene’s SET domain, which is critical
that DNMT3A mutations have a relatively less potent pathogenic for DNA binding. 126,127 EZH2 mutations confer a negative prognosis
effect than some other genes (e.g., TET2 mutations, which are less in MDS that appears to be independent of other prognostic factors,
frequent in the general population but more frequent in MDS). including the IPSS score, in part because they tend not to be associ-
DNTM3A mutations appear to be negatively correlated with ated with specific clinical characteristics that are incorporated into
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mutations in certain other genes, particularly SRSF2 and ASXL1, these systems. 79
and in low-risk MDS they seem to have a positive correlation with
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SF3B1 mutations. There is evidence that DNMT3A mutations
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confer a poor prognosis in cytogenetically normal AML, but that IDH Genes
prognostic significance so far has not been convincingly shown to
apply to DNMT3A-mutated MDS. The isoforms of isocitrate dehydrogenase, encoded by IDH1 and
IDH2, are responsible for the conversion of isocitrate to α-KG, which
as above is used by TET2 in the conversion of 5mC to 5hmC.
ASXL1 Mutations in IDH1 and IDH2 lead to enzymes with neomorphic
activity that convert α-KG to d-2-hydroxyglutarate, which accumu-
ASXL1 codes for a polycomb chromatin-binding protein and is lating data suggests is an oncometabolite that can inhibit both TET2
involved in epigenetic regulation of gene expression. It acts as a and other epigenetic enzymes, including prolyl hydroxylases and a
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co-activator of the retinoic acid receptor and directly interacts with number of histone demethylases. Mutations in IDH1/2 and other
chemical modifiers of histones (e.g., NCOA1, a histone acetyltrans- members of the IDH pathway (including WT1) have repeatedly been
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ferase, and LSD1, a histone demethylase). ASXL1 mutations occur shown to be important in AML, but IDH mutations are relatively
in about 10% to 29% of total MDS and myeloproliferative neoplasm infrequent in MDS, occurring in 5% or fewer of patients. 79,80 Both
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(MPN), 17% of AML, and 40% of CMML. 114 IDH1 and IDH2 mutations can cooccur with most other recurrent
The specific mechanisms by which ASXL1 mutations affect the mutations besides TET2, with which they are essentially mutually
development of MDS are not clear. The first mice engineered to have exclusive.
constitutive ASXL1 germline insufficiency survived to adulthood
with relatively mild lymphopenia and modest splenomegaly, and did
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not develop myelodysplasia. Subsequently, ASXL1 mutations were Transcription Factor Genes
found to confer global reduction H3K27 trimethylation by disrupt-
ing normal recruitment of polycomb recessive complex 2 (PRC2), Transcription factors represent a third class of genes commonly
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which places the H3K27 mark in vivo. This was followed by a more mutated in MDS. Similar to epigenetic and splicing genes, mutated
physiologic attempt at conditional ASXL1 knockout in murine transcription factors can have pleiotropic effects on a number of gene
hematopoietic cells, which did induce abnormal myeloid differentia- targets, and these mutations are indeed also often early events in
tion that was compounded by additional loss of TET2. In this study, MDS pathogenesis.
ASXL1-deficient cells displayed differential expression of a set of
genes largely related to hematopoietic differentiation. 117
In humans, most MDS-associated ASXL1 mutations affect the RUNX1
C-terminal portion of the protein, specifically the plant homeo
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protein interaction domain. This observation has led to speculation RUNX1 (formerly known as AML1) is the transcription factor gene
that the mutant protein retains DNA-binding activity and thus exerts most commonly mutated in MDS, and its biology is complex. It
a dominant-negative effect on wildtype ASXL1, which may not have encodes the alpha subunit of the core binding transcription factor
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been captured in the mouse experiments. In studies of MDS cohorts, and is involved in determining the lineage fate of HSCs. RUNX1
investigators have observed that ASXL1 mutations co-occur less fre- was initially identified as one of the genes involved in two different
quently with certain other recurrent genetic lesions, particularly common pathogenic translocations: t(8;21), found in AML, and
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DNTM3A and JAK2. On the other hand, ASXL1 mutations have t(12;21), found in acute lymphoblastic leukemia. 131,132 Subsequently,
been found to cooccur with both RUNX1 and TET2 abnormali- germline point mutations in RUNX1 were identified in autosomal
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ties. The most recent rigorous studies suggest that ASXL1 muta- dominant familial platelet disorder with propensity for AML, and
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tions have a modestly poor prognosis, but tend to occur in patients later as somatic events in both sporadic AML and MDS. Reflecting
with low IPSS scores who would otherwise be felt to have indolent the complexity of RUNX1 biology, mutations occurring throughout
disease, perhaps suggesting a more profound pathogenic effect the gene, can be either monoallelic or biallelic, and can be frameshift
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than might be suspected. 79 insertions or deletions or nonsense or missense substitutions.
However, most mutations appear to have an inactivating effect on
RUNX1 function, either by affecting the DNA-binding RUNT
EZH2 domain or by disrupting the C-terminal protein interaction domain.
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Many of the remaining mutations outside these regions appear to
EZH2 encodes the catalytic subunit of PRC2, which promotes the affect RUNX1 interactions with epigenetic regulators like MLL,
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di- and trimethylation of lysine 27 on histone 3 (H3K27). Locally, thereby affecting histone methylation. Both clonal and subclonal
methylated H3K27 results in closed chromatin and transcriptional RUNX1 mutations appear to confer a poor prognosis in MDS
repression, and global H3K27 trimethylation in particular is associ- patients, irrespective of other prognostic factors. 78
ated with reduced pluripotency and cellular senescence, suggesting a
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role for EZH2 in regulation of cell fate. Recent studies have shown
that α-KG also regulates relative levels of methylation at this locus, ETV6
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suggesting a possible convergence with the TET2/IDH pathway.
EZH2 resides on the long arm of chromosome 7, and its loss has ETV6 encodes an ets-like transcription factor with mostly repressive
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been hypothesized to be at least part of the reason 7q− is such a activity. It is situated on the short arm of chromosome 12, and its