Department of Medicine, Division of Hematology/Oncology; Program in Molecular Medicine; Program in Gene Function and Expression
GA-Binding Protein Transcription Factor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Hematology | Hemic and Lymphatic Diseases | Neoplasms | Oncology
Hematopoietic stem cells (HSCs) are the source of all blood lineages, and HSCs must balance quiescence, self-renewal, and differentiation to meet lifelong needs for blood cell development. Transformation of HSCs by the breakpoint cluster region-ABL tyrosine kinase (BCR-ABL) oncogene causes chronic myelogenous leukemia (CML). The E-twenty six (ets) transcription factor GA binding protein (GABP) is a tetrameric transcription factor complex that contains GABPalpha and GABPbeta proteins. Deletion in bone marrow of Gabpa, the gene that encodes the DNA-binding component, caused cell cycle arrest in HSCs and profound loss of hematopoietic progenitor cells. Loss of Gabpalpha prevented development of CML, although mice continued to generate BCR-ABL-expressing Gabpalpha-null cells for months that were serially transplantable and contributed to all lineages in secondary recipients. A bioinformatic screen identified the serine-threonine kinase protein kinase D2 (PRKD2) as a potential effector of GABP in HSCs. Prkd2 expression was markedly reduced in Gabpalpha-null HSCs and progenitor cells. Reduced expression of PRKD2 or pharmacologic inhibition decreased cell cycling, and PRKD2 rescued growth of Gabpalpha-null BCR-ABL-expressing cells. Thus, GABP is required for HSC cell cycle entry and CML development through its control of PRKD2. This offers a potential therapeutic target in leukemia.
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DOI of Published Version
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2312-7. doi: 10.1073/pnas.1212904110. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Yang, Zhongfa; Zhang, Haojian; Ma, Leyuan; Peng, Cong; Chen, Yaoyu; Wang, Junling; Green, Michael R.; Li, Shaoguang; and Rosmarin, Alan G., "GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2" (2013). Program in Gene Function and Expression Publications and Presentations. 212.