A number sign (#) is used with this entry because of evidence that susceptibility to myelodysplastic syndrome (MDS) may be conferred by heterozygous germline mutations in several genes, including the the GATA2 gene (137295) on chromosome 3q21, the TERC gene (602322) on chromosome 3q26, and the TERT gene (187270) on chromosome 5p15.

Myelodysplastic syndrome is also associated with somatic mutation in several genes, including TET2 (612839) on chromosome 4q24, SF3B1 (605590) on chromosome 2q33, ASXL1 (612990) on chromosome 20q11, and GNB1 (139380) on chromosome 1p36.

See also chromosome 5q deletion syndrome (153550) and monosomy 7 myelodysplasia and leukemia syndromes (M7MLS1, 252270; M7MLS2, 619041), which are characterized by myelodysplasia.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematologic stem cell disorders characterized by ineffective hematopoiesis resulting in low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia (AML; 601626). Blood smears and bone marrow biopsies show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of 1 or more lineages (erythroid, myeloid, megakaryocytic). MDS can be subdivided into several categories based on morphologic characteristics, such as low-grade refractory anemia (RA) or high-grade refractory anemia with excess blasts (RAEB). Bone marrow biopsies of some patients show ringed sideroblasts (RARS), which reflects abnormal iron staining in mitochondria surrounding the nucleus of erythrocyte progenitors (summary by Delhommeau et al., 2009 and Papaemmanuil et al., 2011).

Germline Mutations

Hahn et al. (2011) analyzed 50 candidate genes in 5 families with a predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML; 601626), and in 3 of the families they identified a heritable heterozygous missense mutation in the GATA2 gene (T354M; 137295.0002) that segregated with disease and was not found in 695 nonleukemic ethnically matched controls. In another family, they identified a heterozygous 3-bp deletion in GATA2 (137295.0014) in a father and son with MDS.

Among 799 adults with various myeloid neoplasms, including presumed acquired myelodysplastic syndrome, bone marrow failure, and other related disorders, Nagata et al. (2018) identified 26 different heterozygous germline variants in the SAMD9 or SAMD9L genes. The patients and variants were ascertained from public whole-exome sequencing databases. Most of the variants were missense, although there were a few frameshift or nonsense changes. The variants occurred throughout the gene, but tended to be located more in the N terminus compared to pediatric cases. In vitro functional expression studies of some, but not all, of the missense variants resulted in enhanced cell proliferation compared to controls, indicating a loss-of-function (LOF) effect. These variants were not subject to somatic reversion, as observed in pediatric patients with gain-of-function mutations in theses genes. Many MDS patients had secondary somatic hits in other genes that likely contributed to the development of the disorder. Nagata et al. (2018) hypothesized that the late onset of MDS in these patients resulted from protracted acquisition of secondary hits in other genes associated with myeloid malignancies. Overall, germline variants in one or the other of these 2 genes were identified in about 4% of patients with adult-onset MDS and 3% with bone marrow failure.

Feurstein et al. (2022) performed focused whole-exome sequencing of 233 genes or next-generation sequencing of a subset of 77 genes associated with inherited hematopoietic malignancies, bone marrow failure, telomere biology, DNA repair, immunodeficiencies, RASopathies, cancer predisposition syndromes, or congenital cytopenias in the blood of 404 patients (average age, 59 years; range, 11-75 years) with MDS and their related hematopoietic stem cell (HSC) donors. Germline pathogenic or likely pathogenic mutations were identified in 28 patients, and in 20 patients the mutation was shared with their HSC donor. Likely pathogenic or pathogenic mutations were identified in 33% of patients aged 11-20 years; 8% of patients aged 21-30 years, 31-40 years, and 71-80 years; 7% of patients aged 51-60 years; and 6% of patients aged 41-50 years and 61-70 years. Of the 28 mutations, there were 26 truncating mutations, 1 in-frame deletion, and 1 missense mutation. There were no differences in HSC transplant outcomes between patients who shared a gene mutation with their donor and those that did not. Feurstein et al. (2022) noted that this study and prior similar studies showed that adults less than 40 years of age with germline mutations and MDS often have mutations in genes associated with DNA repair, telomere biology, and bone marrow failure, whereas patients between the ages of 40 and 70 years with germline mutations and MDS often carry mutations in genes associated with telomere biology and general cancer predisposition.

Somatic Mutations

Using whole-exome sequencing, Papaemmanuil et al. (2011) identified 64 different somatic mutations in various genes in bone marrow cells of 9 patients with low-grade myelodysplastic syndromes, 8 of whom had refractory anemia with ringed sideroblasts. These findings indicated that MDS is genetically heterogeneous. Six of the 9 patients carried 1 of 2 heterozygous mutations in the SF3B1 gene (605590): a lys700-to-glu (K700E) substitution or a his662-to-gln (H662Q) substitution. Targeted resequencing of this gene found that 72 (20%) of 354 patients with MDS had mutations in the SF3B1 gene. The majority (68%) of the patients with mutations had refractory anemia with ringed sideroblasts, although 6% had refractory anemia with excess blasts. Mutations in the SF3B1 gene were also found less frequently in bone marrow from patients with other chronic myeloid disorders, such as primary myelofibrosis (254450), essential thrombocythemia (187950), and chronic myelomonocytic leukemia (CMML; see 607785), as well as in acute myeloid leukemia (AML; 601626). Mutations were also found in about 1% of solid tumors. SF3B1 mutations were located throughout the gene, but were clustered in exons 12 to 15; K700E was the most common mutation, accounting for 59 (55%) of the 108 variants observed. Alignment and in silico studies indicated that the mutations were not severely deleterious, suggesting that the mutant proteins retain structural integrity and some function. Gene expression profiling studies suggested a disturbance of mitochondrial gene networks in stem cells from MDS patients with SF3B1 mutations. Clinically, MDS patients with SF3B1 mutations had higher median white cell count, higher platelet count, higher erythroid hyperplasia, lower proportion of bone marrow blasts, and overall longer survival compared to those without SF3B1 mutations, suggesting a more benign phenotype.

Walter et al. (2011) identified 13 somatic heterozygous mutations in the DNMT3A gene (602769) in 8% of bone marrow samples derived from 150 patients with MDS. Four of the mutations occurred at residue arg882, in the methyltransferase domain. Only 2 of the mutations resulted in truncation, and mRNA expression of the missense mutations was similar to wildtype. Although the survival of patients with DNMT3A mutations was worse than of those without these mutations, the overall sample was small. In all, 58% of patients with a DNMT3A mutation progressed to AML, compared to 28% without a mutation. Analysis of the bone marrow cells showed that the mutations were present in nearly all of the cells, although the myeloblast count was less than 30% for most samples, suggesting that DNMT3A mutations are very early genetic events in MDS and may confer a clonal advantage to cells with the mutation. The findings also indicated that epigenetic changes contribute to MDS pathogenesis.

Graubert et al. (2012) identified heterozygous somatic mutations affecting residue ser34 (S34F or S34Y) of the U2AF1 gene (191317) in bone marrow cells derived from 13 (8.7%) of 150 cases of MDS. A mutation was initially found by whole-genome sequencing in an index patient followed by sequencing of the U2AF1 coding regions in a larger patient cohort. One patient from the larger cohort also had a heterozygous Q157R mutation in U2AF1 on the same allele. All patients had de novo occurrence of the disease. Ser34 is a highly conserved residue within a zinc finger domain, which may be important for RNA binding. In vitro functional expression studies in minigene reporter assays showed that the mutant cDNA caused an increase in splicing and exon skipping of other genes compared to wildtype, consistent with a gain of function. There was no difference in U2AF1 mRNA or protein levels in bone marrow from patients with mutations compared to those without mutations. There was also no difference in survival or myoblast count between patients with U2AF1 mutations and those without mutations. However, those with U2AF1 mutations had an increased probability of progression from MDS to secondary acute myeloid leukemia (sAML; see 601626) (p = 0.03); the frequency of a U2AF1 mutation was 15.2% in those who progressed to sAML, compared to 5.8% in those who did not. The findings suggested that a defect in splicing may result in altered isoform and gene expression patterns that give rise to cancer.

For discussion of an association between MDS and somatic mutation in the GNB1 gene, see 139380.

Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F (147796.0001) homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the Janus kinase-2 (JAK2; 147796) mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms.