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

eLife

Lillian F Conover¹  Scott J Rodig²  Donna Neuberg³  Mignon L Loh³  Outi Kilpivaara⁴  Hagop M Kantarjian⁵  A Thomas Look⁵  Kristen Stevenson⁶  Guillermo Garcia-Manero⁷  Carlos E Bueso-Ramos⁸  Wen-Shu Wu⁹  Stefan Heinrichs^1,10 

[1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States;Center for Cell Therapies, Children’s Hospital Oakland Research Institute, Oakland, United States;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States;Department of Hematopathology, MD Anderson Cancer Center, Houston, United States;Department of Leukemia, MD Anderson Cancer Center, Houston, United States;Department of Medical Genetics, University of Helsinki, Helsinki, Finland;Department of Pathology, Brigham and Women’s Hospital, Boston, United States;Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States;Department of Pediatrics, University of California, San Francisco, San Francisco, United States;Institute of Transfusion Medicine, University Hospital Essen, Essen, Germany;

关键词: Myelodysplastic Syndromes;    MYBL2;    20q CDR;   

DOI  :  10.7554/eLife.00825

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown