Gene expression profiles of infant acute lymphoblastic leukaemia and its prognostically distinct subsets

Authors

  • Sanjive Qazi,

    1. Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN
    2. Bioinformatics Program, Gustavus Adolphus College, St. Peter, MN
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  • Fatih M. Uckun

    1. Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN
    2. Developmental Therapeutics Program, Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, CA
    3. Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
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Fatih M. Uckun, MD, PhD, Childrens Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles, PO Box 27367, Los Angeles, CA 90027-0367, USA. E-mail: fmuckun@chla.usc.edu

Summary

This study compared the gene expression profiles of primary leukaemic cells from infants versus children with acute lymphoblastic leukaemia (ALL). Our analyses provided unprecedented evidence that remarkably different pathognomonic transcriptomes dominate the biology of infant versus paediatric high risk ALL. The genetic signature of infant ALL is characterized by concomitant overexpression of mitogenic and anti-apoptotic genes, some of which have been associated with early relapse in ALL. Our study demonstrated that primary leukaemia cells from infant ALL patients expressed significantly higher levels of genes for cytokines that mediate their biological effects through stimulation of the JAK-STAT signal transduction pathway including interleukin 1a, interleukin 1b, interleukin 2, and interleukin 7. We further showed that the JAK/STAT signalling pathway is constitutively active in CD10 infant ALL cells and treatment with a JAK3 inhibitor or a pan-JAK kinase inhibitor effectively triggered their apoptosis. These findings identified JAK3 as an attractive molecular target for disrupting the constitutively deregulated anti-apoptotic STAT3 and STAT5 signalling pathways in infant ALL cells.

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