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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4210-4218.
Prepublished online as a Blood First Edition Paper on August 17, 2004; DOI 10.1182/blood-2004-01-0103.
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Submitted January 21, 2004
Accepted July 26, 2004
Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities
Guibin Chen, Weihua Zeng, Akira Miyazato, Eric Billings, Jaroslaw P Maciejewski, Sachiko Kajigaya, Elaine M Sloand, and Neal S Young*
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
* Corresponding author; email: youngn{at}nhlbi.nih.gov.
Aneuploidy, especially monosomy 7 and trisomy 8, is a frequent cytogenetic abnormality in the myelodysplastic syndrome (MDS). Chromosomal abnormalities in general predict prognosis, and patients with monosomy 7 and trisomy 8 have distinctly different clinical courses, responses to therapy, and survival probabilities. To determine disease-specific molecular characteristics, we analyzed the gene expression pattern in purified CD34 hematopoietic progenitor cells obtained from MDS patients with monosomy 7 and trisomy 8 using Affymetrix GeneChips. Two methods were employed: standard hybridization with RNA from pooled patient samples, and a small sample RNA amplification protocol for the limited amounts of RNA available from individual cases; results were comparable between these two techniques. Microarray data were confirmed by gene amplification and flow cytometric measurement of expression of specific genes using individual patient samples. Genes related to hematopoietic progenitor cell proliferation and blood cell function were dysregulated in CD34 cells of both monosomy 7 and trisomy 8 MDS. Additionally, there were distinctive gene expression patterns that distinguished the two karotypes. In trisomy 8, up-regulated genes were primarily involved in immune and inflammatory response (such as TGF- and TGF-receptor), signal transduction (IGF, IGFR1, MYD118, and Rad51), and cell-cycle control (CCNE1 and CDK2), and down-regulated genes have been implicated in apoptosis inhibition. CD34 cells in monosomy 7 showed up-regulation of genes inducing leukemia transformation and tumorigenesis (HOX9A, BRCA2, and PLAB) and apoptosis (TRAIL and TRAIL-DR5), and down-regulation of genes controlling cell growth and differentiation (SPHAR, p21, MAP, and GATA). These results imply distinct molecular mechanisms for monosomy 7 or trisomy 8 MDS and implicate specific pathogeneic pathways.
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