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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 29, pages 423–432 (2015)Cite this article

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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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Acknowledgements

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. 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).

Author Contributions

AEC and JMH designed and performed experiments, analyzed data and wrote the paper. DSW and CPL designed experiments and wrote the paper.

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Author notes

  1. D S Wechsler and C P Lavau: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA

    A E Conway, J M Haldeman & D S Wechsler

  2. Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    D S Wechsler & C P Lavau

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  1. A E Conway
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  2. J M Haldeman
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  4. C P Lavau
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Correspondence to D S Wechsler.

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Conway, A., Haldeman, J., Wechsler, D. et al. A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias. Leukemia 29, 423–432 (2015). https://doi.org/10.1038/leu.2014.221

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