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dc.contributor.authorYang, Zhongfa
dc.contributor.authorZhang, Haojian
dc.contributor.authorMa, Leyuan
dc.contributor.authorPeng, Cong
dc.contributor.authorChen, Yaoyu
dc.contributor.authorWang, Junling
dc.contributor.authorGreen, Michael R.
dc.contributor.authorLi, Shaoguang
dc.contributor.authorRosmarin, Alan G.
dc.date2022-08-11T08:10:15.000
dc.date.accessioned2022-08-23T17:01:25Z
dc.date.available2022-08-23T17:01:25Z
dc.date.issued2013-02-05
dc.date.submitted2013-02-14
dc.identifier.citationProc Natl Acad Sci U S A. 2013 Feb 5;110(6):2312-7. doi: 10.1073/pnas.1212904110. <a href="http://dx.doi.org/10.1073/pnas.1212904110">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1212904110
dc.identifier.pmid23345428
dc.identifier.urihttp://hdl.handle.net/20.500.14038/44005
dc.description.abstractHematopoietic 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23345428&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1073/pnas.1212904110
dc.rights<p>Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.</p>
dc.subjectGA-Binding Protein Transcription Factor
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectGenetics and Genomics
dc.subjectHematology
dc.subjectHemic and Lymphatic Diseases
dc.subjectNeoplasms
dc.subjectOncology
dc.titleGABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume110
dc.source.issue6
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1212&amp;context=pgfe_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pgfe_pp/212
dc.identifier.contextkey3703918
refterms.dateFOA2022-08-23T17:01:25Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathpgfe_pp/212
dc.contributor.departmentProgram in Gene Function and Expression
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Medicine, Division of Hematology/Oncology
dc.source.pages2312-7


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