title: HOXA9 is required for survival in human MLL-rearranged acute leukemias.
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-AML and 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.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Faber
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Krivtsov
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Stubbs
authors.forename: Renee
authors.initials: R
authors.lastname: Wright
authors.forename: Tina N
authors.initials: TN
authors.lastname: Davis
authors.forename: Marry
authors.initials: M
authors.lastname: van den Heuvel-Eibrink
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D051379:Mice; D009154:Mutation / Q000502:physiology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016019:Survival Analysis; D035602:Transcriptional Elongation Factors; D054928:Validation Studies as Topic
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D035602:Transcriptional Elongation Factors; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase