MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy
Stefan Heinrichs,
Lillian F Conover,
Carlos E Bueso-Ramos,
Outi Kilpivaara,
Kristen Stevenson,
Donna Neuberg,
Mignon L Loh,
Wen-Shu Wu,
Scott J Rodig,
Guillermo Garcia-Manero,
Hagop M Kantarjian,
A Thomas Look
Affiliations
Stefan Heinrichs
Institute of Transfusion Medicine, University Hospital Essen, Essen, Germany; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
Lillian F Conover
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
Carlos E Bueso-Ramos
Department of Hematopathology, MD Anderson Cancer Center, Houston, United States
Outi Kilpivaara
Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Kristen Stevenson
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States
Donna Neuberg
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States
Mignon L Loh
Department of Pediatrics, University of California, San Francisco, San Francisco, United States
Wen-Shu Wu
Center for Cell Therapies, Children’s Hospital Oakland Research Institute, Oakland, United States
Scott J Rodig
Department of Pathology, Brigham and Women’s Hospital, Boston, United States
Guillermo Garcia-Manero
Department of Leukemia, MD Anderson Cancer Center, Houston, United States
Hagop M Kantarjian
Department of Leukemia, MD Anderson Cancer Center, Houston, United States
A Thomas Look
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States
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.
