PRKD2 Serine-Threonine Kinase, an Essential Effector of Gabp Transcription Factor, Is Required for Development of Chronic Myelogenous Leukemia

Abstract

AbstractAbstract 1672Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm (MPN) caused by transformation of hematopoietic stem cells (HSCs) by the BCR-ABL oncogene. CML is associated with excessive proliferation of HSCs and massive expansion of the myeloid cell pool. GABP is an ets-related transcription factor that controls critical genes in myeloid and lymphoid development, and has been implicated in control of HSC growth. GABP is an obligate multimeric transcription factor that includes the DNA-binding ets component, GABPα, along with various GABPβ partner proteins. We conditionally deleted Gabpa in mouse bone marrow and found that Gabpa cells have a profound growth disadvantage due to cell cycle arrest in HSCs. In a mouse model of CML, animals transplanted with BCR-ABL-infected bone marrow developed massive myeloid cell expansion and died with a MPN. Induced deletion of Gabpa prevented development of CML, yet mice continued to produce mature BCR-ABL-expressing granulocytes for months without apparent illness. BCR-ABL+ cells were transplantable into secondary recipients without development of CML, and contributed to all hematopoietic lineages, thereby confirming expression of BCR-ABL by long-term HSCs. We used a bioinformatic approach to analyze GABP-bound genes that are upregulated in both human and mouse LSCs compared to normal HSCs. Among 115 GABP-bound, CML-associated genes, we identified Protein Kinase D2 (PRKD2) as a candidate effector of GABP. PRKD2 is a diacyl glycerol- and Protein Kinase C-activated serine-threonine kinase that has been implicated in cancer, but has not previously been associated with HSC functions or CML. Deletion of Gabpa markedly reduced PRKD2 expression in normal HSCs and progenitor cells. In vitro growth of BCR-ABL+ bone marrow cells was prevented by Gabpa deletion, but growth was partially rescued by forced expression of PRKD2. Knockdown and pharmacologic inhibition of PRKD2 blocked cell cycle entry of BCR-ABL+ cells. We conclude that Gabp is required for HSC cell cycle entry and for development of CML, and that these effects of GABP are mediated, in part, by PRKD2. These findings suggest that PRKD2 kinase may serve as a novel therapeutic target in leukemia. Disclosures:No relevant conflicts of interest to declare.