UMMS Affiliation

Department of Medicine, Division of Hematology/Oncology; Program in Molecular Medicine; Program in Gene Function and Expression

Date

2-5-2013

Document Type

Article

Medical Subject Headings

GA-Binding Protein Transcription Factor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Disciplines

Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Hematology | Hemic and Lymphatic Diseases | Neoplasms | Oncology

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 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.

Rights and Permissions

Citation: 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

Comments

Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.

Related Resources

Link to Article in PubMed

PubMed ID

23345428

 
 

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