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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2744-2752. Prepublished online as a Blood First Edition Paper on July 28, 2009; DOI 10.1182/blood-2008-09-179812. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2008-09-179812v1 114/13/2744    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Edwards, H. Articles by Ge, Y. PubMed PubMed Citation Articles by Edwards, H. Articles by Ge, Y. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia Holly Edwards1,*, Chengzhi Xie1,2,*, Katherine M. LaFiura1, Alan A. Dombkowski3, Steven A. Buck4, Julie L. Boerner1,5, Jeffrey W. Taub1,4,6, Larry H. Matherly1,5, and Yubin Ge1,2,5,6 1 Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI; 2 College of Life Science, Jilin University, Changchun, People's Republic of China; 3 Institute of Environmental Health Sciences, Wayne State University, Detroit, MI; 4 Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit; and Departments of 5 Pharmacology and 6 Pediatrics, Wayne State University School of Medicine, Detroit, MI RUNX1 (AML1) encodes the core binding factor subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in acute leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in acute leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with acute megakaryocytic leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases. Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)–kinase. Transcriptional regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antileukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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