A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias

• Authors: Amanda E. Conway, Duke University; Jonathan M. Haldeman, Duke University; Dan Wechsler, Emory University; Catherine P. Lavau, Duke University
• Journal Title: LEUKEMIA
• Volume: Volume 29, Number 2
• Publisher: NATURE PUBLISHING GROUP | 2015-02-01, Pages 423-432
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/leu.2014.221
• Subjects: Health Sciences, Oncology; Biology, Genetics; Biology, Cell
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Hematology; NUCLEAR EXPORT SIGNAL; ACUTE LYMPHOBLASTIC-LEUKEMIA; SUBCELLULAR-LOCALIZATION; DIFFERENTIAL EXPRESSION; HOMEOBOX GENES; GENOME-WIDE; FUSION; PROTEIN; CELLS; OVEREXPRESSION

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.