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Author Notes:

Daniel S. Wechsler, MD, PhD, Duke University Medical Center, 397 Hanes House, DUMC Box 102382 Durham, NC 27710, Phone: (919) 684-3401, Fax: (919) 681-7950, dan.wechsler@duke.edu

A.E.C. and J.M.H. designed and performed experiments, analyzed data and wrote the paper. D.S.W. and C.P.L. designed experiments and wrote the paper.

We appreciate the helpful critiques, comments and suggestions of Chi Dang and Rob Wechsler-Reya. We thank Jay Hess for providing the Hoxa9-LUC construct.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by NCI R01 CA 109281 (DSW), a V Foundation/Applebee’s Grant (DSW), a St. Baldrick’s Research Grant (DSW) and a Hyundai Hope Grant (CPL).

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

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

Tools:

Journal Title:

LEUKEMIA

Volume:

Volume 29, Number 2

Publisher:

, Pages 423-432

Type of Work:

Article | Post-print: After Peer Review

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.

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