title: Overexpression of GATA1 confers resistance to chemotherapy in acute megakaryocytic Leukemia.
abstract: It has been previously shown that acute myeloid leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with acute megakaryocytic leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.
authors.affiliation: Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: John Timothy
authors.initials: JT
authors.lastname: Caldwell
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.forename: Alan A
authors.initials: AA
authors.lastname: Dombkowski
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buck
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy / Q000235:genetics*; D046228:Microarray Analysis; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D014635:Valproic Acid