MYBL2 Is a Candidate Tumor Suppressor Gene In MDS

Abstract 1865

Cytogenetic changes, mainly deletions, can be found in about 30–50% of patients with Myelodysplastic Syndromes (MDS). To identify a tumor suppressor candidate within a commonly deleted region on chromosome 20q, we performed gene expression analysis on CD34+ bone marrow cells obtained from 8 patients with a 20q aberration and 18 with a normal karyotype. However, we were unable to identify genes that were significantly differentially expressed in aberrant 20q karyotype as compared to normal karyotype MDS patients. In contrast, a comparison of CD34+ cells from all MDS cases analyzed (n=26) with CD34+ cells obtained from normal bone marrow (n=4) revealed 108 genes that were differentially expressed. Interestingly, one of the top-scoring genes was MYBL2, which is located on chromosome 20q. MYBL2 levels were downregulated more than two-fold in 18 out of 26 cases. RNAi-mediated knockdown of MYBL2 in CD34+ normal bone marrow cells revealed a signature of genes functionally associated with the G2/M cell cycle phase confirming the well-documented role of MYBL2 as key transcription factor governing the onset of cell division. We hypothesize that in a subset of MDS cases the control of cell division may be impaired by low levels of MYBL2 such that altered cell fates established during cell division in early hematopoietic stem and progenitor cells will lead to clonal expansion with imbalanced or impaired differentiation. Indeed, gene set enrichment analysis revealed a strong enrichment of MYBL2 signature genes in MDS CD34+ cells. In support of a potential role as tumor suppressor, resequencing of MYBL2 (144 patients) identified 2 somatic mutations, pinpointing an additional mechanism to reduce expression of normal levels of wild-type MYBL2.