http://hdl.handle.net/1765/16099

scopus: 64049095814



HOXA9 is required for survival in human MLL-rearranged acute leukemias


Article
volume 113, issue 11 pp 2375-2385.
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Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biologic characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes, including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL- rearranged and MLL-germline leukemias using RNA interference. Gene expression profiling after HOXA9 suppression demonstrated co-down-regulation of a program highly expressed in human MLL- AMLand murine MLL-leukemia stem cells, including HOXA10, MEIS1, PBX3, and MEF2C. We demonstrate that HOXA9 depletion in 17 human AML/ALL cell lines (7 MLL-rearranged, 10 MLL-germline) induces proliferation arrest and apoptosis specifically in MLL-rearranged cells (P = .007). Similarly, assessment of primary AMLs demonstrated that HOXA9 suppression induces apoptosis to a greater extent in MLL-rearranged samples (P = .01). Moreover, mice transplanted with HOXA9-depleted t(4;11) SEMK2 cells revealed a significantly lower leukemia burden, thus identifying a role for HOXA9 in leukemia survival in vivo. Our data indicate an important role for HOXA9 in human MLL-rearranged leukemias and suggest that targeting HOXA9 or downstream programs may be a novel therapeutic option. © 2009 by The American Society of Hematology.



Keywords


Automatically Extracted Terms
  • hoxa 9 suppression
  • leukemia
  • expression
  • hoxa 9
  • suppression
  • shrna
  • hoxa 9 expression
  • figure
  • analysis
  • signi
  • blood
  • mll-rearranged
  • control
  • transduction
  • murine
  • myeloid
  • induction
  • signi ficantly
  • transduced
  • erasmus mc


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