Genomic landscape of CD34 ⁺ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers

Abstract

Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34+ hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 proteincoding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34 + versus CD34 − cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.prognostic stratification | clonal evolution | gene mutation pattern

Splice factor mutations and alternative splicing as drivers of hematopoietic malignancy

“…While several MDS and MDS/MPN studies have noted that mutations SF genes are largely mutually exclusive (i.e. providing an overlapping function or existing within the same pathway), most studies also report occasional (1–4%) concurrent mutations in different SF . This is consistent with the proposal by Mian et al .…”

Immunohistochemical loss of 5‐hydroxymethylcytosine expression in acute myeloid leukaemia: relationship to somatic gene mutations affecting epigenetic pathways

“…In our series, we did not find an association between any additional mutations and 5hmC status, except for two cases with EZH2 mutations that also showed loss of 5hmC. EZH2 is a histone methyltransferase that is mutated in ~6% of MDS cases . The role of EZH2 mutation in leukaemogenesis is poorly understood, and it is unclear whether disruption of the epigenetic modification performed by EZH2 would affect the TET2 pathway .…”

Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

“…Somatic alterations affecting the same amino acids as the germline alterations are boxed. Somatic alterations reported in the literature include ones associated with MDS 33,35,36 , AML 32,33,37–39 , CMML 40 , immature T cell ALL 34 , mature T cell ALL 41 , B cell precursor ALL 42,43 , hypodiploid ALL 10 , multiple myeloma 44 , colorectal adenocarcinoma 30,31 and melanoma 45 . Truncating alterations, including nonsense, frameshift and splice-site changes, are shown in bold.…”