title: GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells.
abstract: The master regulatory transcription factor GATA-2 triggers hematopoietic stem and progenitor cell generation. GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and GATA2 overexpression portends a poor prognosis for AML. However, the constituents of the GATA-2-dependent genetic network mediating pathogenesis are unknown. We described a p38-dependent mechanism that phosphorylates GATA-2 and increases GATA-2 target gene activation. We demonstrate that this mechanism establishes a growth-promoting chemokine/cytokine circuit in AML cells. p38/ERK-dependent GATA-2 phosphorylation facilitated positive autoregulation of GATA2 transcription and expression of target genes, including IL1B and CXCL2. IL-1β and CXCL2 enhanced GATA-2 phosphorylation, which increased GATA-2-mediated transcriptional activation. p38/ERK-GATA-2 stimulated AML cell proliferation via CXCL2 induction. As GATA2 mRNA correlated with IL1B and CXCL2 mRNAs in AML-M5 and high expression of these genes predicted poor prognosis of cytogenetically normal AML, we propose that the circuit is functionally important in specific AML contexts.
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Koichi R
authors.initials: KR
authors.lastname: Katsumura
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ong
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: DeVilbiss
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Rajendran
authors.initials: R
authors.lastname: Sanalkumar
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Electronic address: ehbresni@wisc.edu.
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D057895:Haploinsufficiency; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases