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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Conway, AE; Haldeman, JM; Wechsler, DS; Lavau, CP

Published Date

  • February 2015

Published In

Volume / Issue

  • 29 / 2

Start / End Page

  • 423 - 432

PubMed ID

  • 25027513

Pubmed Central ID

  • 25027513

Electronic International Standard Serial Number (EISSN)

  • 1476-5551

Digital Object Identifier (DOI)

  • 10.1038/leu.2014.221

Language

  • eng

Conference Location

  • England