title: A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias.
abstract: The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10-mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Conway
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Haldeman
authors.affiliation: 1] Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA [2] Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Wechsler
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Lavau
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D005810:Multigene Family; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014158:Transcription, Genetic; D020298:U937 Cells; D000097606:Exportin 1 Protein
chemical_list: D005231:Fatty Acids, Unsaturated; D018398:Homeodomain Proteins; D028884:Karyopherins; D008156:Luciferases; D015514:Oncogene Proteins, Fusion; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C114359:AF10-CALM fusion protein, human; C088144:HoxA protein; C038753:leptomycin B