Page 1065 - Hematology_ Basic Principles and Practice ( PDFDrive )

948 Part VII Hematologic Malignancies

mutations in single genes, has been increasingly well characterized,
and clinical tests for recurrent mutations are becoming increasingly Splicing Factor Mutations
available, though as discussed later, it appears that not all mutations
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have equal clinical relevance. Finally, epigenomic alterations—global Genes encoding splicing factors, which excise introns to create mature
aberrations in histone and chromatin modification—are common in messenger RNA (mRNA) transcripts, are the most commonly
MDS, and are often, though not always, associated with mutations mutated class of genes in MDS, with between half and two-thirds of
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in genes involved in epigenetic regulation. 75 patients harboring such a mutation. As opposed to most of the other
classes of mutations discussed here, which occur in other malignan-
cies with significant frequency, splicing factor mutations are rarer in
Somatic Mutations other cancers than MDS, and some have unique associations with
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specific morphologic phenotypes. Splicing factor mutations tend to
Of the types of genetic abnormalities found in MDS, acquired muta- be mutually exclusive within MDS clones, and most of the affected
tions in individual genes are the most recently recognized; they are genes encode proteins that comprise the E/A splice site recognition
also the most frequent, currently estimated to be present in around complex that acts at the 3′ end of pre-mRNA, suggesting that the
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80% of MDS patients. Although certain environmental exposures mutations converge on a shared biologic pathway. Exactly how
increase the risk of acquiring potentially deleterious mutations, most splicing factor mutations predispose to the development of MDS,
are acquired randomly, either spontaneously (e.g., deamination of and whether they can help predict aspects of natural history or
cytosine to uracil), during DNA replication before cell division, or treatment response, remain areas of active investigation.
during DNA repair.
One of the central challenges of understanding the genetics of
MDS has been determining which mutations contribute to the SF3B1
pathogenesis of the disease and which do not. Accumulating evidence
has shown that HSCs acquire nonsynonymous exonic mutations with SF3B1 encodes the U2 small nuclear riboprotein complex (snRNP)
translational consequences at a rate of about one mutation per responsible for 3′ branch site recognition and is the most frequently
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decade. Since the incidence of MDS increases with age, HSPCs mutated splicing factor gene. SF3B1 mutations can be found in
from an average MDS patient should typically contain between 5–10 about 20% to 30% of all MDS patients; there is a particularly
such mutations (though the actual number varies widely between strong association with ring sideroblast morphology, with mutations
patients), against a background of hundreds of noncoding single found in 60% to 85% of patients with RARS or RARS-T and
nucleotide variations. The vast majority of these mutations, both substantial percentages of other MDS subtypes in which ring
coding and noncoding, are of no pathogenic consequence and are sideroblasts can be found. 86,87 The most common mutations are
thus termed passenger mutations, while a minority, the so-called driver missense substitutions that change lysine to glutamate at codon
mutations, actually contribute to the development of the disease. 77 700, with other smaller hotspots in the same vicinity. These muta-
Distinguishing driver mutations from passenger mutations is not tions all occur within a cluster of 26 nonrepeating HEAT domains
always trivial. Passenger mutations, without conferring clonal advan- that are thought to be involved in binding of SF3B1 to other
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tage, tend not to recur with any significant frequency in cohorts of members of the U2 snRNP. As with other splicing factor muta-
MDS patients; however, whereas a few driver mutations are relatively tions, they tend to be heterozygous and imply a gain of function.
common in MDS, many have been found in only a small fraction How exactly the mutations affect MDS pathogenesis is not com-
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(<5%) of cases, suggesting novel mechanisms of disease pathogenesis. pletely clear, but they are often acquired early in disease develop-
Similarly, whereas noncoding mutations are unlikely to contribute to ment, tend not to be associated with complex karyotypes, and tend
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pathogenesis and can thus be ignored when analyzing MDS genomes, not to be associated with poor-prognosis mutations. SF3B1 muta-
the majority of coding mutations, even those present within a major- tions are clinically associated with a distinct phenotype of isolated,
ity of cells in the malignant clone, are also nonpathogenic and are transfusion-dependent anemia with preserved white blood cell and
simply artifacts captured by an aging HSPC. Classifying a mutation platelet counts relative to SF3B1-wildtypes, as well as a lower risk
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as a driver thus involves accumulating evidence that the mutation of progression to AML. Indeed, in larger studies of MDS cohorts,
occurs recurrently in MDS, that its putative function could plausibly SF3B1 mutations appear to confer an improvement in relative
contribute to MDS pathogenesis, and, in the best-case scenario, that survival, making them somewhat unique among MDS-associated
this function can be recapitulated using in vitro or in vivo models. mutations. 80
Large-scale genomic studies of MDS cohorts have shown that many
of the recurrently mutated genes can be segregated into one of a few
functional categories, 78–81 and this functional characterization has in SRSF2
turned revealed insights about how an MDS clone develops over time.
Genes affecting RNA splicing (SRSF2, SF3B1, U2AF1) are the most SRSF2 encodes a member of the serine/arginine (SR)-rich family of
commonly mutated and tend to be early events in MDS pathogenesis. pre-mRNA splicing factors that interacts with the U2 and U1 com-
Genes affecting epigenetic regulation (TET2, ASXL1, EZH2, ponents of the spliceosome. After SF3B1, it is the second-most
DNMT3A) are the next-most commonly mutated and also tend to commonly mutated splicing factor, with mutations present in 10%
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occur early. On the other hand, mutations in genes for growth factors to 15% of MDS and 40% of CMML. The overwhelming majority
(NRAS, JAK2) tend to occur late and in subclonal populations. of mutations are heterozygous missense substitutions for proline at
These observations have contributed to an overarching model of codon 95, implying a gain of function. A small minority of in-frame
how sequential somatic mutations cooperate to bring about MDS. insertions or deletions affects the same region. SRSF2 mutations
In this model, early mutations in splicing factors and epigenetic genes co-occur with several other mutations, many of which are also fre-
do little to affect proliferation or differentiation on their own, but quently found in CMML, including TET2, ASXL1, CUX1, IDH2,
rather create a permissive environment for the acquisition of subse- and STAG2. In contradistinction to patients with SF3B1 mutations,
quent mutations in genes that confer proliferative advantages or patients with SRSF2 mutations tend to have more dysplasia in the
blocks in differentiation. The latter group of mutations contributes granulocytic lineage and less in the erythroid lineage, and patients
more directly to the clinical features of MDS, but the former is consequently tend to have a less prominent transfusion requirement,
responsible for its tendency towards genomic and epigenomic insta- more enrichment in the RAEB subtypes, and, at least in some studies,
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bility, which in turn may contribute to the disease’s poor response to a greater risk of progression to AML. This phenotype is more het-
treatment. This section is a brief summary of our current understand- erogeneous than that associated with SF3B1, but most studies have
ing of some of the most important genes and pathways that are nevertheless shown that SRSF2 mutations appear to confer an inferior
recurrently deranged in MDS. 82 prognosis. 91