| First Author | Yang ZF | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 6 | Pages | 2312-7 |
| PubMed ID | 23345428 | Mgi Jnum | J:194335 |
| Mgi Id | MGI:5473451 | Doi | 10.1073/pnas.1212904110 |
| Citation | Yang ZF, et al. (2013) GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. Proc Natl Acad Sci U S A 110(6):2312-7 |
| abstractText | 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. |
