Page 1068 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 951

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role in hematologic malignancy has been best characterized by its tyrosine kinase mutations found in MDS, but still only occur in
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involvement in recurrent translocations, including t(3;12)(q26;p13) about 5% of cases and as mentioned earlier, tend to begin as sub-
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and deletions of 12p. In MDS, however, both missense and inac- clonal, proproliferative events that frequently drive the transition to
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tivating frameshift point mutations have been described as well. AML. Best known for its role in MPNs, JAK2 is mutated in about
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There is some data that the missense mutations, which mostly cluster 3% to 5% of MDS, particularly RARS-T and CMML. JAK2
in the DNA-binding ETS domain, have a dominant negative effect mutations in MDS tend not to be associated with overproduction of
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on the wildtype allele. However, whether malignant transformation mature hematopoietic cells as they are in MPNs, likely as a conse-
requires ETV6 activity below a critical threshold remains unclear, as quence of concomitant biologic defects contributing to ineffective
not all frameshift mutations occur with loss of heterozygosity (and hematopoiesis. 159
some frameshifts can confer dominant negative function as well).
ETV6 mutations are relatively rare events in MDS, occurring in at
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most 5% of cases; recently, familial cases of MDS and AML because Cohesin Complex Genes
of inherited ETV6 mutations have also been described. 39
Genes encoding members of the cohesin complex family, including
RAD21, STAG2, SMC3, and SMC1A, are each mutated in a small
GATA2 minority of MDS cases, but collectively, cohesin mutations can be
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found in about 10% of MDS. Their physiologic role is in the
GATA2 encodes a transcription factor with pleiotropic effects in early maintenance of chromatid structural fidelity, particularly during
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hematopoietic progenitor cells. In contrast to most other genes mitosis. How cohesin complex mutations affect MDS pathogenesis
described here, acquired mutations in GATA2 are quite rare, but there is not completely understood, since they do not appear to directly
are a number of clinical syndromes associated with germline GATA2 promote chromosomal instability. Clinical studies, however, have
mutations, several of which involve a risk of developing MDS and shown that they appear to be disproportionately associated with
AML. These include Emberger syndrome (congenital lymphedema multilineage dysplasia, and confer inferior survival and an increased
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and risk of AML), autosomal dominant monocytopenia and risk of progression to AML. 161
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mycobacterial infection syndrome, and dendritic cell, monocyte, B
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and natural killer (NK) lymphoid deficiency syndrome. In addi-
tion, GATA2 mutations have also been described in kindreds with no Other Genes
accessory phenotype beyond a strong history of early-onset MDS/
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AML. Several phenotypic components appear to be dependent on The genes described previously collectively account for the majority
the type of mutation. For instance, nearly all patients who develop of mutations found recurrently in MDS, but this list is certainly not
MDS or AML have mutations in or immediately 5′ to the second exhaustive. Even very recent, broad surveys of patients with MDS
zinc finger domain, which tend to be missense substitutions predicted using the most updated panels of gene mutations and high-resolution
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to affect DNA binding. On the other hand, a second group of FISH and karyotyping have shown that between 10% and 20% of
patients with truncating frameshift mutations in the N-terminal patients lack a detectable genetic abnormality. 78–81 There are multiple
region of the gene tend to present at younger ages with more pro- possible explanations for this observation. For example, some of
nounced immune deficits, but have a lower risk of MDS or AML. these patients may have other types of aberrations not captured by
Although the mechanism by which these patients develop MDS is sequencing or karyotyping, such as small copy number abnormali-
not completely clear, the subset of patients with GATA2 germline ties that might be detected by SNP arrays, which are not routinely
mutations who develop MDS or AML has been observed to acquire performed in clinical practice. More likely, however, many of these
ASXL1 mutations with frequency much greater than would be patients probably have mutations in genes that are less frequently
expected to occur by chance. 146 altered in MDS pathogenesis. Some of these mutations are in path-
ways represented by other, better-known genes; for example, rare
mutations have been described in PTPN11, a tyrosine phosphatase
TP53 that acts as a downstream effector in the RAS pathway, and in
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BRAF, better known for its association with melanoma and hairy
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TP53 mutations occur in about 10% of patients with MDS, and as cell leukemia. Similarly, rare mutations have been described in
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in other settings imply a poor prognosis and response to therapy. EED and SUZ12, other components of the PRC2 that affiliate with
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They are closely associated with a complex karyotype and tend not EZH2 and collectively interact with ASXL1. Other times, MDS
to cooccur with other recurrent driver mutations. 147,148 They fre- can occur in the setting of mutations in genes better known for being
quently cooccur with del(5q) and may represent a progression associated with other diseases, such mutations in CBL, a gene better
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pathway for patients with 5q− syndrome. They are also frequently known for its association with juvenile myelomonocytic leukemia
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found in t-MDS and AML. Recently, a small series of patients with that encodes an E3 ubiquitin ligase responsible for degrading several
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t-AML showed that TP53 mutations present in the leukemia were tyrosine kinases. Finally, mutations are occasionally described in
detectable in samples collected 3–6 years earlier, which in at least two relatively novel gene classes, including genes encoding the G-protein
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patients predated their original chemotherapy. This suggests that subunits GNAS and GNB1 and the DNA repair enzymes
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the expansion of rare preexisting clones harboring TP53 mutations hOGG1, XRCC3, and XPD. Some patients may have mutations
may be the leukemogenic mechanism in at least some patients with in other genes that have yet to be described. While it is unlikely
therapy-related disease, rather than accumulation of DNA damage that a major, frequently mutated pathway remains undiscovered
induced by the chemotherapy itself. in MDS, study of these low-frequency, “long-tail” mutations may
yield valuable further insights into the molecular pathogenesis of the
disease.
Tyrosine Kinases and Growth Factor Receptors
Mutations in tyrosine kinase and growth factor receptor genes are Karyotypic Abnormalities
typically associated with proproliferative signals and occur in a wide
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range of myeloid malignancies, including AML (FLT3 ), MPNs Chromosomal abnormalities, larger-scale genetic aberrations that can
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(JAK2 and MPL ), and mast cell disorders (KIT). While they be detected on either karyotype or FISH, are also common events in
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do occur in MDS, they are usually late, subclonal events that often MDS. The most common types of abnormalities in MDS are
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mark progression to secondary AML. A few of these deserve specific deletions or duplications of very large chromosomal regions; as
mention. Activating mutations in NRAS are the most frequent opposed to some other hematologic cancers, translocations and