MYBL2 Is a Sub-haploinsufficient Tumor Suppressor Gene in Myeloid Malignancy (RNA)

A dosage-dependent role for tumor suppressor genes in the initiation of myeloid malignancies remains controversial. Here we show that MYBL2 is expressed at sharply reduced levels in CD34+ cells from most patients with myelodysplastic syndrome (MDS; 65%; n=26). In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors led to clonal dominance by these sub-haploinsufficient cells, affecting all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. Thus, downregulation of MYBL2 activity to levels below those predicted by classical haploinsufficiency drives the clonal expansion of hematopoietic progenitors in a large fraction of human MDS cases.

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Heinrichs S, Conover LF, Bueso-Ramos CE, Kilpivaara O, Stevenson K, Neuberg D, Loh ML, Wu WS, Rodig SJ, Garcia-Manero G, Kantarjian HM, Look AT