HOXA9 is required for survival in human MLL-rearranged acute leukemias
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||Hox protein, HoxA9 protein, RNA interference, acute granulocytic leukemia, acute leukemia, animal cell, animal model, apoptosis, article, cancer cell culture, cancer survival, cell cycle arrest, cell proliferation, chromosome rearrangement, clinical assessment, controlled study, gene expression profiling, germ line, human, human cell, immunosuppressive treatment, in vivo study, leukemia cell, mixed lineage leukemia protein, mouse, nonhuman, priority journal, protein depletion, receptor down regulation, stem cell, transcription factor, transcription factor HoxA10, transcription factor MEIS1, transcription factor Mef2c, transcription factor PBX3, transplantation, unclassified drug|
|Persistent URL||dx.doi.org/10.1182/blood-2007-09-113597, hdl.handle.net/1765/16099|
Faber, J, Krivtsov, A.V, Stubbs, M.C, Wright, R, Davis, T.N, van den Heuvel-Eibrink, M.M, … Armstrong, S.A. (2009). HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood, 113(11), 2375–2385. doi:10.1182/blood-2007-09-113597