MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

Abstract

A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20–30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these ‘sub-haploinsufficient’ cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies.DOI: http://dx.doi.org/10.7554/eLife.00825.001

B- myb is an essential regulator of hematopoietic stem cell and myeloid progenitor cell development

“…In addition, CMPs and GMPs in which B-myb is disrupted in vitro proliferate more slowly. These results are consistent with previous reports documenting a role for B-myb in S/G 2 /M progression and checkpoint control (20,22,25,46,47). A similar phenotype is also observed in the zebrafish crash&burn (crb) mutant (48), which harbors a loss of function mutation in bmyb.…”

“…Although the hematopoietic compartment of younger animals did not show significant changes, the phenotype of a subset of the aged animals, particularly those subjected to transplant-induced replicative stress, is similar to that of B-myb KO mice immediately following pIpC administration. These data suggest that B-myb haploinsufficiency cooperates with other genetic lesions to cause disease, in contrast to that which occurs in the absence of B-myb expression or in cells expressing levels of B-myb that mirror those seen in CD34 + MDS cells (approximately 20-30% of normal) (46). A better understanding of the role of B-myb in normal hematopoietic cell development will hopefully allow us to define its role in disease states that result in defective hematopoiesis, such as MDS.…”

“…MYBL2 is expressed at 20-30% of normal levels in CD34 + cells of ∼65% of MDS cases, irrespective of karyotype (46,54). Consistent with the notion that partial loss of MYBL2 expression is associated with MDS, it has recently been shown that B-myb heterozygous mice develop MDS and other myeloproliferative neoplasms at 12-24 mo of age (54).…”

Down-regulation of EZH2 expression in myelodysplastic syndromes

“…Haploinsufficiency of the important hematopoietic transcription factor GATA2 also plays an important role in MDS and AML [18]. MYBL2 [19], a cell cycle regulatory tumor suppressor gene located in a commonly deleted region of chromo-some 20q, has also been shown to be downregulated via the same mechanism in MDS and myeloproliferative neoplasms. In this scenario, our findings together with previous studies of EZH2 in MDS by Nikoloski et al [7] provide evidence that EZH2 haploinsufficiency is associated with MDS.…”

Genetic characterization of acquired aplastic anemia by targeted sequencing

“…11 MYBL2 is a candidate tumor suppressor gene that is located in the commonly deleted region of MDS patients with del20q, 12 and haploinsufficiency of this gene predisposes to MDS in a mouse model.…”