GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2.

Abstract

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 GABPα and GABPβ 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 Gabpα prevented development of CML, although mice continued to generate BCR-ABL-expressing Gabpα-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 Gabpα-null HSCs and progenitor cells. Reduced expression of PRKD2 or pharmacologic inhibition decreased cell cycling, and PRKD2 rescued growth of Gabpα-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.

• Authors: Zhong-Fa Yang, Haojian Zhang, Leyuan Ma, Cong Peng, Yaoyu Chen, Junling Wang, Michael R Green, Shaoguang Li, Alan G Rosmarin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 6 Pg. 2312-7 (Feb 05 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23345428 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• GA-Binding Protein Transcription Factor
• Gabpa protein, mouse
• Piperazines
• Protein Kinase D2
• Protein Kinase Inhibitors
• Pyrimidines
• Imatinib Mesylate
• Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Cell Cycle
• GA-Binding Protein Transcription Factor (deficiency, genetics, metabolism)
• Gene Expression
• Hematopoietic Stem Cells (drug effects, metabolism, pathology)
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, etiology, genetics, metabolism)
• Mice
• Mice, Transgenic
• Piperazines (pharmacology)
• Protein Kinase D2
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (genetics, metabolism)
• Pyrimidines (pharmacology)