Genomic Landscape Of CD34~+Hematopoietic Cells In Myelodysplastic Syndrome And Gene Mutation Profiles As Prognostic Markers

Myelodysplastic syndrome (MDS) includes a group of diseasescharacterized by dysplasia of bone marrow myeloid lineages withineffective hematopoiesis and frequent evolution to acute myeloidleukemia (AML). Whole genome sequencing was performed in CD34+hematopoietic stem/progenitor cells (HSPC) from8cases of refractoryanemia with excess blasts (RAEB), the high risk subtype of MDS. Thenucleotide substitution patterns were found similar to those reported inAML, and mutations of96protein-coding genes were identified. Clonalarchitecture analysis revealed presence of subclones in6of8cases,while mutation detection of CD34+versus CD34-cells revealedheterogeneity of HSPC expansion status. With39marker genesbelonging to8functional categories, mutations were analyzed in196MDS cases including mostly RAEB (n=89) and refractory cytopenia withmultilineage dysplasia (RCMD, n=95). At least one gene mutation wasdetected in91.0%of RAEB, contrarily to that in RCMD (55.8%),suggesting a higher mutational burden in the former group. Geneabnormality patterns differed between MDS and AML, with mutations ofactivated signaling molecules and NPM1being rare while those ofspliceosome more common in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression freesurvival.