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1348 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1349

Somatic mutations can have important clinical implications for For example, SF3B1 mutant patients are less likely to have cytogenetic
patients with MDS and the physicians who treat them, but their inter- abnormalities, including complex karyotypes, and are less likely to
pretation can be challenging. Several factors may influence the clini- have other mutations in genes associated with a poor prognosis. Only
cal significance or recurrent gene mutations. These include the type mutations in DNMT3A cooccur with SF3B1 mutations more often than
of mutation present (e.g., missense, nonsense, splicing, or frameshift), would be predicted by chance alone, suggesting a cooperative interac-
the configuration of the mutations (e.g., homozygous, heterozygous, tion between these lesions. 90,141 SF3B1-mutant MDS may represent its
hemizygous, or compound heterozygous), the fraction of disease cells own nosologic entity based on its common clinical features and patterns
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that contain the mutations (i.e., presence in the dominant clone ver- of comutation regardless of WHO subtype. Mutation of SF3B1 is also
sus a subclone), the mutations that coexist in that patient and if these common in chronic lymphocytic leukemia (CLL) where it occurs in 15
mutations are in the same clone or a sister clone, and whether mutations to 20 percent of cases (Chap. 92). However, in contrast with MDS, these
add information above and beyond what can be learned by looking at mutations in CLL are often subclonal or acquired after initial diagnosis
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more readily accessible clinical variables like age, blast proportion, and and are associated with treatment resistance and a poor prognosis.
blood counts. Despite these complexities, there are several scenarios in SF3B1 hotspot mutations are enriched in uveal melanoma and can be
which specific gene mutations can inform the clinical care of patients found in various other solid tumors at lower frequency, demonstrating
with clonal cytopenias like MDS. that it is not a tissue-specific oncogene. 144,145
Splicing Factors The most frequently mutated class of genes SRSF2 is the second most frequently mutated splicing factor,
in patients with MDS encode splicing factor proteins involved in the present in 10 to 15 percent of MDS and 40 percent of CMML cases. It
excision of introns and the ligation of exons from maturing pre-mRNA encodes a serine-arginine–rich protein that interacts with the U2 and
strands. There are at least eight recurrently mutated splicing factor U1 components of the spliceosome. The predominant mutation in this
genes identified in MDS and nearly two-thirds of patients will carry at gene is a missense substitution of the proline at codon 95, although
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mutation of a member of this gene family. Splicing factor mutations small insertions and deletions at this position that conserve the read-
are largely mutually exclusive. Patients with one splicing factor muta- ing frame have also been reported. As with SF3B1, mutations are hete-
tion rarely have a mutation in another suggesting that these lesions are rozygous to a wild-type allele suggesting a very specific gain or change
either not tolerated in combination or, more likely, have a common of function. SRSF2 mutations cooccur with mutations of several other
mechanism of action. Thus, a disease stem cell that acquires a second genes, such as TET2, ASXL1, CUX1, IDH2, and STAG2, many of which
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splicing factor mutation would gain no selective advantage and may are also enriched in patients with CMML. SRSF2 mutations are gener-
well develop a selective disadvantage as a consequence of that second ally associated with an inferior prognosis.
mutation. Despite a presumed common pathogenic role, patients with U2AF1 is the third frequently mutated splicing factor, present in
mutations in different splicing factor genes often have very disparate approximately 12 percent of patients. Like SF3B1 and SRSF2, mutations
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clinical phenotypes. This is partially because disease manifestations are heterozygous to a wild-type allele and occur as missense mutations
are often determined by the effect of driver mutations in the differen- at fixed hotspots. The affected amino acids at codons 34 and 157 are
tiating progeny of disease stem cells. Some may induce profound dys- in the zinc finger DNA-binding regions of the protein. 140,146 U2AF1
plasia while others promote lineage-specific proliferation, for example. encodes an auxiliary factor in the U2 spliceosome responsible for the
Different splicing factor mutations may also be associated with certain recognition of the AG splice acceptor dinucleotide at the 3′ end of
clinical phenotypes because of their distinct patterns of comutation introns. U2AF1 mutations appear to affect splicing in reporter assays
with other MDS-related genes. 90,135,141 These comutations may, for exam- and transgenic mouse models, but how these changes confer a selective
ple, drive the disease manifestations or prognosis. If there is a common advantage to mutant cells is not well understood. 140,147 Clinically, U2AF1
mechanism by which splicing factor mutations drive the development mutations are associated with shorter overall survival and increased
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of MDS, it is not yet well understood. These mutations are not unique to risk of transformation to acute leukemia. Patient with del(20q) may
MDS as they can be found in other malignancies, including some solid be enriched or U2AF1 mutations. Several additional splicing factors
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tumors, where they occur at low frequency. Several studies have identi- can be mutated in MDS, including ZRSR2, SF1, and U2AF2. Most of
fied changes in splicing efficiency and gene expression associated with these appear to harbor loss-of-function mutations, but remain largely
splicing factor mutations, but these effects are subtle and do not readily exclusive of mutations in other splicing factors, suggesting a shared
identify a downstream pathogenic mechanism. pathogenic mechanism.
SF3B1 is the most frequently mutated splicing factor gene and
encodes the U2 small nuclear riboprotein complex (snRNP) subunit Epigenetic Regulators
responsible for branch site recognition. Mutations of SF3B1 are pres- Epigenetic changes, defined as heritable covalent modifications of
ent in 20 to 30 percent of patients and are the only somatic mutations chromatin that do not alter the DNA base sequence, play a role in the
associated with a favorable prognosis. The pattern of mutation of SF3B1 development of MDS and other malignancies. Methylation of cytosine
suggests an oncogenic gain or change of function for its encoded residues in DNA represents one form epigenetic modification that can
protein. Mutations are always heterozygous to an intact wild-type allele be dysregulated in MDS. Specifically, patients may have global DNA
and are relatively conservative missense substitutions at very specific hypomethylation, but will demonstrate hypermethylation in specific
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hotspots. These mutations occur in the middle of several consecutive regions such as the CpG islands (areas rich in CG dinucleotides) found
HEAT protein domains of which the K700E substitution is the most at or near gene promoters. These epigenetic marks have been associated
common, accounting for more than half of all mutations of SF3B1. with a closed chromatin configuration and relative silencing of nearby
Clinically, mutations of SF3B1 are very tightly associated with the pres- genes. The simplistic explanation is that aberrant DNA methylation
ence of ring sideroblasts (Fig. 87–3). More than 85 percent of patients leads to the pathogenic silencing of critical tumor-suppressor genes and
with RARS or RARS-t will have an SF3B1 mutation. These mutations is, therefore, oncogenic. Hypomethylating agents, which are inhibitors
are common in patients with other subtypes of MDS, like refractory of the DNA methyltransferases that catalyze cytosine methylation, have
cytopenia with multilineage dysplasia, when ring sideroblasts are pres- been presumed to undo the silencing of these tumor-suppressor genes
ent. SF3B1 mutations have been associated with a more favorable prog- leading to therapeutic benefit. However, it is not certain that hypometh-
nosis but it is unclear if this is independent of other known risk factors. ylating agents work in this way. It is known that several genes involved

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