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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1570-1581.
Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-06-2219.
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Submitted June 6, 2005
Accepted October 1, 2005
Differential gene expression, GATA1 target genes and the chemotherapy sensitivity of down syndrome megakaryocytic leukemia
Yubin Ge, Alan A Dombkowski, Katherine M LaFiura, Dana Tatman, Ravikiran S Yedidi, Mark L Stout, Steven A Buck, Gita Massey, David L Becton, Howard J Weinstein, Yaddanapudi Ravindranath, Larry H Matherly, and Jeffrey W Taub*
Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA
Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA
Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, USA
Medical College of Virginia, Richmond, Virginia, USA
University of Arkansas, Little Rock, Arkansas, USA
Massachusetts General Hospital, Boston, Massachusetts, USA
Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, USA; Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA
* Corresponding author; email: jtaub{at}med.wayne.edu.
Down syndrome (DS) children with acute megakaryocytic leukemia (AMkL) have very high survival rates compared to non-DS AMkL patients. Somatic mutations identified in the X-linked transcription factor gene, GATA1, in essentially all DS AMkL cases result in the synthesis of a shorter (40 kDa) protein (GATA1s) with altered transactivation activity and may lead to altered expression of GATA1 target genes. Using the Affymetrix U133A microarray chip, we identified 551 differentially expressed genes between DS and non-DS AMkL samples. Transcripts for the bone marrow stromal cell antigen 2 (BST2) gene, encoding a transmembrane glycoprotein potentially involved in interactions between leukemia cells and bone marrow stromal cells, were 7.3-fold higher (validated by real-time PCR) in the non-DS compared to the DS group. Additional studies confirmed GATA1 protein binding and transactivation of the BST2 promoter, however, stimulation of BST2 promoter activity by GATA1s was substantially reduced compared to the full length GATA1. CMK sublines, transfected with the BST2 cDNA and incubated with HS-5 bone marrow stromal cells, exhibited up to 1.7-fold reduced ara-C-induced apoptosis, compared to mock-transfected cells. Our results demonstrate that genes which account for differences in survival between DS and non-DS AMkL cases may be identified by microarray analysis, and that differential gene expression may reflect relative transactivation capacities of the GATA1s and full-length GATA1 proteins.
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