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1352 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1353

hearing loss, alveolar proteinosis, and dermatologic abnormalities. be associated with a poor prognosis. 204,205 Cohesins bind to chromatin
Penetrance is variable and patients with one syndrome often will have in a large complex believed to protect chromatid structure and shep-
features of the others. Several cases of congenital neutropenia or appar- herd chromosomes through mitosis. However, mutations of this com-
ently de novo MDS in childhood have been ascribed to germline GATA2 plex are not associated with chromosomal instability in MDS. Instead,
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mutations in the absence of other syndromic features. However, unlike they identify patients more likely to have multilineage dysplasia.
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RUNX1 and ETV6 mutations, mutations of GATA2 are only very rarely The pathogenic mechanism of cohesin mutations in myeloid disorders
somatic events. remains poorly understood.
TP53 TP53 mutations are present in approximately 10 percent of Other Classes of Mutated Genes Several other classes of genes
MDS cases and are strongly associated with a poor prognosis indepen- are recurrently mutated in MDS, including DNA repair enzymes, RNA
dent of other risk factors. Most patients with mutations of TP53 will helicases, and members of the G-protein signaling pathway. The long
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have a complex karyotype and tend to have fewer point mutations in tail of recurrent, but rarely mutated genes in MDS suggest that dysplasia
other typical MDS genes. Patients with del(5q) are more likely to have is common final phenotype that can be caused by a variety of different
a TP53 mutation, particularly in the context of a complex karyotype, pathogenic abnormalities, each with their own degree of severity, risk of
suggesting pathologic synergy between these abnormalities. 90,135 Unfor- progression, and variation in clinical presentation.
tunately, treatment with either hypomethylating agents or allogeneic
hematopoietic stem cell transplantation (AHSCT) fails to rescue the Microenvironmental Changes
adverse outcomes associated with mutations of TP53. 192–194 Not all abnormalities identified in the marrow of patients with MDS
Mutations of Growth Factor Signaling Pathway Genes Muta- are intrinsic to the clonal cells that give rise to the disease. There are
tions of receptor tyrosine kinase genes are common in proliferative many microenvironmental alterations that contribute to the distorted
myeloid disorders, such as FLT3 in AML, KIT in mast cell neoplasms, hematopoiesis that is characteristic of MDS. Marrow cytokine levels
and of the receptor gene MPL in MPN, but only rarely present in MDS. are altered in many cases. Circulating monocyte colony-stimulating
Instead, several genes encoding downstream signaling proteins are factor (M-CSF) is increased in some patients with MDS, AML, and
more frequently mutated in MDS. Many of these mutations are asso- other hematologic malignancies. Interleukin (IL)-1α and granulo-
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ciated with proliferative features and often presage more advance dis- cyte-macrophage colony-stimulating factor (GM-CSF) levels have been
ease or progression to secondary AML. Signaling pathway mutations undetectable in most patients. IL-6, granulocyte colony-stimulating
are typically mutually exclusive, indicating some redundancy in func- factor (G-CSF), and erythropoietin concentrations have been variable.
tion and are more common in CMML where monocytic proliferation Tumor necrosis factor (TNF) concentrations has been inversely related
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is a defining feature. In MDS, these mutations are frequently present in to hematocrit. Stem cell factor, a multilineage hematopoietin, can be
minor disease subclones demonstrating that they were acquired later in decreased in some patients. 208
the course of disease. Despite their small abundance, signaling pathway The neoplastic clone may induce activation of the innate immune
mutations are often predictive of transformation and shorter overall system. Loss of miRNAs 145 and 146a from the CDR of chromosome 5q
survival. 195,196 lead upregulation of toll-interleukin receptor adaptor protein (TIRAP)
Activating NRAS mutations are the most common in this category, and tumor receptor-associated factor (TRAF) 6, members of the innate
but found in only 5 to 10 percent of cases. These lesions are associated immune signaling pathway downstream of toll-like receptors. Toll-like
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with excess blasts and thrombocytopenia. The E3-ubiquitin ligase receptors may also be targets of somatic mutations leading to nuclear
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CBL regulates tyrosine kinase receptors by marking them for degrada- factor (NF)-κB activation. Myeloid-derived suppressor cells, distinct
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tion. CBL mutations that impair this function are found in 3 to 5 per- from the clonal disease cells, may contribute to the altered cytokine
cent of MDS cases and are associated with monocytosis. 198,199 Somatic microenvironment and promote disordered hematopoiesis. 210
mutations of the tyrosine phosphatase encoded by PTPN11 are seen in Dysregulation of the adaptive immune system has also been
very rare cases of MDS and CMML, but are more common in juvenile described. CD40 expression on monocytes is increased, as is CD40L on
myelomonocytic leukemia where mutations are often germline lesions T lymphocytes, and has been postulated as being a contributing factor
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and part of a congenital syndrome. 200,201 Other genes that are very rarely to hematopoietic failure in some patients with less-advanced disease.
but recurrently mutated in this pathway include KRAS, BRAF, KIT, and Many patients with MDS will demonstrate oligoclonal T-cell expansion
CBLB. with skewing of Vβ-subunits of the T-cell receptor similar to that seen in
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The V617F mutation in JAK2 is found in 3 to 5 percent of patients aplastic anemia. In patients that respond to immunosuppressive ther-
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with MDS and is exclusive of other signaling pathway mutations. How- apy, this oligoclonality of T cells may be normalized. There likely exists
ever, it does not appear to have prognostic significance and is not asso- substantial pathogenic overlap between aplastic anemia and hypoplastic
ciated with an increased red cell mass as it is in polycythemia vera. MDS. Immunosuppression can improve hematopoiesis in both disor-
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This is likely because JAK2 mutations in MDS are often late events and ders, both can exhibit paroxysmal nocturnal hemoglobinuria (PNH)
coexist with other genetic lesions that result in dysplasia, limiting the clones, and both can have somatic mutations typical of MDS (Chap. 35).
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production of mature red cells. JAK2 mutations are enriched in patients Large granular lymphocyte (LGL) leukemia can cause immune cytope-
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with RARS-t, and MDS/MPN overlap disease. Half of these patients nias and LGL cells are present in some cases of both MDS and aplastic
will carry a JAK2 V617F mutation. This is roughly the same proportion anemia. These lymphocytes can carry somatic mutations of STAT3 indi-
observed in patients with essential thrombocythemia (ET); leading to cating their clonal nature, distinct from the MDS clone. 214
the speculation that RARS-t is a “frustrated” form of ET with dysplasia
caused by the other mutations like those in SF3B1 associated with ring
sideroblasts. Approximately 5 percent of RARS-t patients will instead CLINICAL FEATURES
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have a mutation in MPL, which is similar to the rate at which it occurs
in ET as well (Chap. 85). SYMPTOMS AND SIGNS
Cohesin Genes RAD21, STAG2, SMC3, and SMC1A are recur- Patients can be asymptomatic or, if anemia is more severe, can have pal-
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rently mutated members of the cohesin gene family. Collectively, they lor, weakness, loss of a sense of well-being, and exertional dyspnea.
are mutated in approximately 10 percent of MDS cases, where they may Fatigue is a major complaint that is not necessarily related to degree

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