Journal
BLOOD
Volume 114, Issue 13, Pages 2744-2752Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-09-179812
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Funding
- Karmanos Cancer Institute
- Children's Research Center of Michigan
- Leukemia Research Life
- Children's Leukemia Foundation of Michigan
- National Cancer Institute [CA120772]
- Leukemia & Lymphoma Society
- BPCT Golf Charity
- Sehn Family Foundation
- Dale Meyer Memorial Endowment for Leukemia Research
- Ring Screw Textron Endowed Chair for Pediatric Cancer Research
- Microarray and Bioinformatics Facility Core
- Wayne State University (National Institute of Environmental Health Science [NIEHS]) [P30 ES06639]
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RUNX1 (AML1) encodes the core binding factor alpha 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 delta 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. (Blood. 2009;114:2744-2752)
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