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

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 C...

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Published in:eLife 2013-07, Vol.2, p.e00825-e00825
Main Authors: Heinrichs, Stefan, Conover, Lillian F, Bueso-Ramos, Carlos E, Kilpivaara, Outi, Stevenson, Kristen, Neuberg, Donna, Loh, Mignon L, Wu, Wen-Shu, Rodig, Scott J, Garcia-Manero, Guillermo, Kantarjian, Hagop M, Look, A Thomas
Format: Article
Language:English
Subjects:
20q CDR
Bone marrow
Cancer
CD34 antigen
Cell cycle
Cell Cycle Proteins - genetics
Chromosome 20
Chromosomes
Cloning
Dosage Compensation, Genetic
Flow cytometry
Gene expression
Genes and Chromosomes
Genes, Tumor Suppressor
Haploinsufficiency
Haploinsufficiency - genetics
Hemopoiesis
Human Biology and Medicine
Humans
Karyotyping
Leukemia
Malignancy
Mutation
MYBL2
Myelodysplastic syndrome
Myelodysplastic Syndromes
Myelodysplastic Syndromes - genetics
Myeloproliferative Disorders - genetics
Phase transitions
RNA-mediated interference
Trans-Activators - genetics
Transcription factors
Transplantation
Tumor suppressor genes
Tumorigenesis
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.00825