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Cytogenetics and molecular genetics

Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes

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Fig. 1: CRM1-AF10 and CRM1Δ-AF10 display leukemogenic activity.
Fig. 2: Impairing the NUP214/CRM1 interaction abrogates leukemia development.

References

  1. Kumon K, Kobayashi H, Maseki N, Sakashita A, Sakurai M, Tanizawa A, et al. Mixed-lineage leukemia with t(10;11)(p13;q21): an analysis of AF10-CALM and CALM-AF10 fusion mRNAs and clinical features. Genes Chromosomes Cancer. 1999;25:33–9.

    Article  CAS  Google Scholar 

  2. Dik WA, Brahim W, Braun C, Asnafi V, Dastugue N, Bernard OA, et al. CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. Leukemia. 2005;19:1948–57.

    Article  CAS  Google Scholar 

  3. Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121:167–78.

    Article  CAS  Google Scholar 

  4. Conway AE, Haldeman JM, Wechsler DS, Lavau CP. A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias. Leukemia. 2015;29:423–32.

    Article  CAS  Google Scholar 

  5. Conway AE, Scotland PB, Lavau CP, Wechsler DS. A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis. Blood. 2013;121:4758–68.

    Article  CAS  Google Scholar 

  6. Bond J, Bergon A, Durand A, Tigaud I, Thomas X, Asnafi V, et al. Cryptic XPO1-MLLT10 translocation is associated with HOXA locus deregulation in T-ALL. Blood. 2014;124:3023–5.

    Article  Google Scholar 

  7. Dong X, Biswas A, Chook YM. Structural basis for assembly and disassembly of the CRM1 nuclear export complex. Nat Struct Mol Biol. 2009;16:558–60.

    Article  CAS  Google Scholar 

  8. Port SA, Monecke T, Dickmanns A, Spillner C, Hofele R, Urlaub H, et al. Structural and functional characterization of CRM1-Nup214 interactions reveals multiple FG-binding sites involved in nuclear export. Cell Rep. 2015;13:690–702.

    Article  CAS  Google Scholar 

  9. Meijerink JP, Cante-Barrett K, Vroegindeweij E, Pieters R. HOXA-activated early T-cell progenitor acute lymphoblastic leukemia: predictor of poor outcome? Haematologica. 2016;101:654–6.

    Article  CAS  Google Scholar 

  10. Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT, et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood. 2006;108:1999–2005.

    Article  CAS  Google Scholar 

  11. Nguyen N, Oakley K, Han Y, Kwok M, Crouch G, Du Y. Interaction with XPO1 is essential for SETBP1 to induce myeloid transformation. Leukemia. 2019;33:2758–62.

    Article  Google Scholar 

  12. Oka M, Mura S, Yamada K, Sangel P, Hirata S, Maehara K, et al. Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes. Elife. 2016;5:e09540.

    Article  Google Scholar 

  13. Oka M, Mura S, Otani M, Miyamoto Y, Nogami J, Maehara K, et al. Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. Elife. 2019;8:e46667.

    Article  Google Scholar 

  14. Lavau CP, Aumann WK, Sze SK, Gupta V, Ripple K, Port SA, et al. The SQSTM1-NUP214 fusion protein interacts with Crm1, activates Hoxa and Meis1 genes, and drives leukemogenesis in mice. PLoS ONE. 2020;15:e0232036.

    Article  CAS  Google Scholar 

  15. Wang AY, Liu H. The past, present, and future of CRM1/XPO1 inhibitors. Stem Cell Invest. 2019;6:6.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

CRM1 plasmids containing mutants in the NUP214 binding region were generously provided by Ralph Kehlenbach and Sarah Port. Pritha Bagchi, PhD and the Emory Integrated Proteomics Core provided assistance with BioID2 Mass Spectrometry. This work was supported by an American Society of Hematology Research Training Award for Fellows (WKA), Hyundai Hope on Wheels Young Investigator Award (WKA and CPL), Hyundai Hope On Wheels Scholar Award (CPL and DSW), the Duke Cancer Institute (CPL), a NIH R03 grant (1R03CA191983-01A1, CPL), Alex’s Lemonade Stand Young Investigator Award (JLH), Pablove Foundation (JLH), Pediatric Cancer Research Foundation (JLH), NHLBI T32 5T32HL007057-37 (WKA), NHLBI T32 5T32HL007057-40 (SKS), a St. Baldrick’s Foundation Research Award (DSW), and the Schiffman Family Foundation. CPL is an INSERM scientist.

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Correspondence to Daniel S. Wechsler or Catherine P. Lavau.

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None of the authors has any direct or indirect commercial financial incentive associated with publishing this article. None of the authors has an affiliation with any organization that, to our knowledge, has a direct interest in the subject matter discussed. The Wechsler Laboratory received financial support from Karyopharm, Inc. several years prior to performing the work described in this manuscript, but no Karyopharm products were used for the studies described here.

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Aumann, W.K., Heath, J.L., Conway, A.E. et al. Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes. Leukemia 35, 876–880 (2021). https://doi.org/10.1038/s41375-020-0998-3

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