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Published on: February 21, 2018
Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic
Yubin Ge1, Alan A Dombkowski, Katherine M LaFiura
1Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute of Environmental Sciences, Wayne State University, Detroit, MI 48201, USA.
Insights
Children with Down syndrome (DS) and acute megakaryocytic leukemia (AMkL) have better survival due to altered GATA1 protein expression. This impacts gene expression, including BST2, influencing leukemia cell response to chemotherapy.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Children with Down syndrome (DS) exhibit significantly higher survival rates when diagnosed with acute megakaryocytic leukemia (AMkL) compared to non-DS AMkL patients.
- Somatic mutations in the GATA1 gene in DS AMkL cases lead to a truncated GATA1s protein, altering its transactivation activity and downstream gene expression.
Purpose of the Study:
- To identify differentially expressed genes between DS and non-DS AMkL using microarray analysis.
- To investigate the role of GATA1s and full-length GATA1 in regulating target genes like BST2 and their impact on leukemia cell apoptosis.
Main Methods:
- Utilized Affymetrix U133A microarray to compare gene expression in DS and non-DS AMkL samples.
- Validated BST2 gene expression using real-time polymerase chain reaction.
- Assessed GATA1 and GATA1s transactivation of the BST2 promoter and their effect on ara-C-induced apoptosis in leukemia cell lines.
Main Results:
- Identified 551 differentially expressed genes between DS and non-DS AMkL.
- BST2 transcripts were significantly higher in non-DS AMkL (7.3-fold).
- GATA1s showed reduced stimulation of BST2 promoter activity compared to full-length GATA1, leading to decreased ara-C-induced apoptosis in BST2-transfected cells.
Conclusions:
- Microarray analysis can identify genes contributing to survival differences in DS AMkL.
- Differential gene expression, particularly of BST2, is linked to the varying transactivation capacities of GATA1s and full-length GATA1.
- Altered BST2 expression may influence chemotherapy response and survival outcomes in AMkL patients.
Abstract:
Children with Down syndrome (DS) with acute megakaryocytic leukemia (AMkL) have very high survival rates compared with 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 polymerase chain reaction) in the non-DS compared with 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 with 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 cytosine arabinoside (ara-C)-induced apoptosis, compared with mock-transfected cells. Our results demonstrate that genes that 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.
