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

Joerg Faber, Andrei V. Krivtsov, Matthew C. Stubbs, Renee Wright, Tina N. Davis, Marry Den Van Heuvel-Eibrink, Christian M. Zwaan, Andrew L. Kung, Scott A. Armstrong

Research output: Contribution to journalArticlepeer-review

279 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2375-2385
Number of pages11
JournalBlood
Volume113
Issue number11
DOIs
Publication statusPublished - 12 Mar 2009
Externally publishedYes

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