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1344 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1345

congenital marrow failure syndromes such as Diamond-Blackfan ane- pulmonary alveolar proteinosis, and disseminated nontuberculous
mia or Shwachman-Diamond syndrome do not carry an increased mycobacterial infections. 54,55 Several distinct clinical syndromes that
MDS risk. 46 include subsets of these features are now known to be caused by germ-
With the exception of the 5q-minus syndrome, males are affected line GATA2 mutations. These include Emberger syndrome comprising
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with MDS up to 1.5 times as often as females. Case-control studies MDS, verrucae, and congenital lymphedema, as well as the MonoMAC
of possible occupational or environmental associations have provided syndrome comprising monocytopenia and nontuberculous mycobacte-
many possible candidates as contributors to MDS, but none other than rial infections. 55–58 Not all patients show overt syndromic features prior
benzene (exposure of ≥40 parts per million [ppm]-years) has been to developing MDS, even as adults, and several pediatric marrow failure
observed consistently. 48–51 Cigarette smoking, and a family history of syndromes can be associated with germlinel GATA2 mutation in the
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hematologic malignancy also seem plausible risk factors. Chemi- absence of syndromic features. 59
cals other than benzene have not been established as causative factors The combined incidence of familial (<2 percent) and therapy-
by epidemiologic studies that fully meet the guidelines proposed by related MDS (~5 to 10 percent) pales in comparison to the frequency
Bradford Hill for causation by an external factor. Moreover, given the of de novo MDS that has age as its dominant predisposing factor. This
requirement for biologic plausibility, such chemicals should be shown may be simply a matter of probability, with aged stem cells being more
to induce the specific driver mutations required to cause MDS. likely to have acquired somatic driver mutations. It may also reflect age-
related changes in the microenvironment or stem cell epigenetic state
as hematopoietic stem cells from elderly persons without disease are
ETIOLOGY AND PATHOGENESIS known to have an exaggerated myeloid differentiation bias. In concert,
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age-related drop out of normal hematopoietic stem cells could lead to
ETIOLOGY oligoclonal, or even monoclonal, hematopoiesis derived from stem cells
The etiologic factors that increase the incidence of MDS are similar to the with weakly selective abnormalities that then serve as fertile ground for
factors affecting the incidence of AML (Chap. 88). Exposure to prolonged cooperating MDS-related somatic mutations. 61
or high levels of benzene, 34,35 chemotherapeutic agents, particularly alky-
lating agents and topoisomerase inhibitors, 36–43 and radiation 44,45 increases
the risk of these clonal hemopathies. These agents may cause DNA dam- PATHOGENESIS
age, impair DNA repair enzymes, and induce loss of chromosome integ- MDS arise from the clonal expansion of a mutated multipotential
rity. Most cases of secondary or posttreatment MDS occur in patients hematopoietic cell. For patients without excess blasts, the cell of origin
treated for a lymphoma or a solid tumor. Increasing reports of MDS as a is presumed to be a lymphohematopoietic pluripotential stem cell based
complication of treatment of myeloid diseases, such as acute promyelo- on the presence of disease-associated driver mutations in cells that
cytic leukemia, may reflect a second clonal myeloid disease from another share the surface protein immunophenotype of functionally defined
primitive hematopoietic cell injured during therapy. The increased life stem cells. Subsequent evolution measured by the acquisition of addi-
43
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span of patients with acute promyelocytic leukemia and other cancers tional mutations takes place in this cellular compartment and can occur
after effective therapy may make these events more common. More com- in more differentiated progenitors, if they confer the capacity for sus-
mon environmental exposures, such as cigarette smoke, may contribute tained self-renewal. Evidence for the clonal nature of MDS is supported
to the likelihood of developing MDS. by studies of skewed X-chromosome inactivation in female patients
Inherited diseases, such as Fanconi anemia, known to predispose heterozygous for glucose-6-phosphate dehydrogenase isoenzymes.
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to AML development occasionally evolve instead into a clonal myeloid The hematopoietic progenitors, 63,64 and sometimes B lymphocytes, of
hemopathy (see Chap. 88, Table 88–1). Other syndromes, of either a such patients had only one isoenzyme present, supporting the concept
46
familial (inherited) or spontaneous nature, have been associated with a of clonal expansion of a neoplastic early progenitor cell. Subsequent
high risk of developing myeloid neoplasms. Germline mutations of the studies confirm the presence of acquired chromosomal abnormalities
hematopoietic transcription factor RUNX1 are associated with a famil- and somatic mutations in hematopoietic progenitors as well as in B and
ial platelet disorder with predisposition at AML (FPD-AML). Affected T lymphocytes in some, but not all, cases. 62,66–72
individuals often have qualitative and quantitative platelet abnormal- This process of clonal expansion takes place in the context of the
ities that precede the development of a more aggressive myeloid neo- marrow microenvironment and host immune response (Chap. 5). These
plasm such as MDS or AML. Transformation typically occurs in the features extrinsic to the cells in the neoplastic clone generate the selec-
third decade of life, but penetrance is variable between individuals tion pressures that drive disease evolution and can significantly influ-
and kinships. The long latency prior to progression suggests that the ence the clinical manifestations of MDS.
acquisition of additional cooperating mutations is required for trans- The hallmark of clonal hematopoiesis is the presence of a somatic
formation. Somatic RUNX1 mutations are also common in de novo and genetic abnormality. Approximately 50 percent of patients with MDS
therapy-related MDS cases highlighting the oncogenic driver nature of will have a grossly abnormal karyotype, typically in the form of a par-
these abnormalities. In contrast, somatic mutations of Fanconi anemia tial or total chromosomal deletion. A fraction of the remaining cases
genes are extremely rare in MDS. Congenital FANC mutations may with a “normal” karyotype will have cryptic cytogenetic abnormalities
instead cause DNA damage and accelerated exhaustion of normal stem that can include small microdeletions and areas of copy number neu-
cells allowing mutant clones to expand more readily. Similarly, inherited tral loss of heterozygosity. This latter phenomenon occurs by mitotic
CCAAT/enhancer binding protein alpha (C/EBPA) mutations, often recombination during cell division and results in acquired uniparen-
associated with eosinophilia, typically predispose to AML without an tal disomy (aUPD) where both copies of a large chromosomal segment
MDS-like clinical phase and are only rarely found as somatic mutations appear to be derived from a single parent. The most common somatic
in MDS. genetic lesions in MDS are mutations of individual genes. More than 50
Congenital mutations of another hematopoietic transcription recurrently mutated genes have been identified with nearly all patients
factor, GATA2, have been linked to familial MDS. The syndromic harboring one or more such mutations (Table 87–2).
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manifestations of germline GATA2 mutations are highly varied and The recurrent nature of many of these genetic events has helped
can include lymphedema, cutaneous warts, sensorineural hearing loss, identify molecular mechanisms associated with the development and

Kaushansky_chapter 87_p1341-1372.indd 1345 9/21/15 11:05 AM