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 ... 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).
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 ... - Mutation in GATA2 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. - 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.