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Leukaemic transformation by CALM–AF10 involves upregulation of Hoxa5 by hDOT1L

Nature Cell Biology volume 8, pages 1017–1024 (2006)Cite this article

An Erratum to this article was published on 01 October 2006

Abstract

Chromosomal translocation is a common cause of leukaemia1 and the most common chromosome translocations found in leukaemia patients involve the mixed lineage leukaemia (MLL) gene2,3. AF10 is one of more than 30 MLL fusion partners in leukaemia4. We have recently demonstrated that the H3K79 methyltransferase hDOT1L contributes to MLL–AF10-mediated leukaemogenesis through its interaction with AF10 (ref. 5). In addition to MLL, AF10 has also been reported to fuse to CALM (clathrin-assembly protein-like lymphoid–myeloid) in patients with T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML)6,7. Here, we analysed the molecular mechanism of leukaemogenesis by CALM–AF10. We demonstrate that CALM–AF10 fusion is both necessary and sufficient for leukaemic transformation. Additionally, we provide evidence that hDOT1L has an important role in the transformation process. hDOT1L contributes to CALM–AF10-mediated leukaemic transformation by preventing nuclear export of CALM–AF10 and by upregulating the Hoxa5 gene through H3K79 methylation. Thus, our study establishes CALM–AF10 fusion as a cause of leukaemia and reveals that mistargeting of hDOT1L and upregulation of Hoxa5 through H3K79 methylation is the underlying mechanism behind leukaemia caused by CALM–AF10 fusion.

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Figure 1: Knockdown of CALM–AF10 in U937 cells impairs their proliferation and leukaemogenesis in vitro and in vivo.
Figure 2: Expression of CALM–AF10 is sufficient to cause mouse bone-marrow cell transformation and hDOT1L has an important role in this process.
Figure 3: Hoxa5 is critical for leukaemic transformation by CALM–AF10.
Figure 4: hDOT1L retains CALM–AF10 in the nucleus.
Figure 5: CALM–AF10 in association with hDOT1L binds to Hoxa5 in both the promoter and downstream regions to mediate local H3K79 methylation.

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Acknowledgements

We thank J.A. Frelinger for providing NOD–SCID mice and E. Kallin for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (NIH) to Y.Z. (GM68804) and L.S. (AI48407, HL72240). Y.O. is a research fellow of Japan Society for the Promotion of Science. L.J. holds a Chercheur National Award from the Fonds de la recherche en Sante du Quebec. Y.Z. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, 27599–7295, NC, USA

    Yuki Okada & Yi Zhang

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599–7295, NC, USA

    Yuki Okada, Qi Jiang, Lishan Su & Yi Zhang

  3. Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599–7295, NC, USA

    Qi Jiang & Lishan Su

  4. Centre de Recherche de L'Hotel-Dieu de Quebec, 9 rue McMahon, Quebec, G1R 2J6, QC, Canada

    Margot Lemieux & Lucie Jeannotte

  5. Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, 27599–7295, NC, USA

    Yi Zhang

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Correspondence to Yi Zhang.

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Okada, Y., Jiang, Q., Lemieux, M. et al. Leukaemic transformation by CALM–AF10 involves upregulation of Hoxa5 by hDOT1L. Nat Cell Biol 8, 1017–1024 (2006). https://doi.org/10.1038/ncb1464

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