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The C-terminal multimerization domain is essential for leukemia development by CBFβ-SMMHC in a mouse knockin model

Leukemia volume 31, pages 2841–2844 (2017)Cite this article

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Chromosome 16 inversion, inv(16), is the signature chromosome abnormality in M4Eo subtype of acute myeloid leukemia (AML), which produces a fusion gene CBFB-MYH11.1 We previously generated a knockin mouse model for CBFB-MYH11 (Cbfb+/MYH11).2 Heterozygous Cbfb-MYH11 knockin mice have definitive hematopoiesis blockage and die at mid-gestation, which is similar to the phenotypes of Runx1−/− and Cbfb−/− mice,3, 4 indicating that CBFβ-SMMHC, the fusion protein encoded by Cbfb-MYH11, dominantly suppresses RUNX1 and CBFβ. Chimeric and conditional Cbfb-MYH11 knockin mice develop AML when they acquire additional mutations.5

An important domain of CBFβ-SMMHC is the C-terminal region of SMMHC, which catalyzes homo-dimerization and multimerization of the fusion protein that may be functionally important.6 To test the function of this region, we previously generated knockin mice that expressed a truncated CBFβ-SMMHC missing C-terminal 95 amino acids. These mice would not develop leukemia, indicating the importance of C-terminal region for leukemogenesis.7

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References

  1. Liu P, Tarle SA, Hajra A, Claxton DF, Marlton P, Freedman M et al. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 1993; 261: 1041–1044.

    Article  CAS  PubMed  Google Scholar 

  2. Castilla LH, Wijmenga C, Wang Q, Stacy T, Speck NA, Eckhaus M et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell 1996; 87: 687–696.

    Article  CAS  PubMed  Google Scholar 

  3. Wang Q, Stacy T, Miller JD, Lewis AF, Gu TL, Huang X et al. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell 1996; 87: 697–708.

    Article  CAS  PubMed  Google Scholar 

  4. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    Article  CAS  PubMed  Google Scholar 

  5. Castilla LH, Garrett L, Adya N, Orlic D, Dutra A, Anderson S et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet 1999; 23: 144–146.

    Article  CAS  PubMed  Google Scholar 

  6. Adya N, Stacy T, Speck NA, Liu PP . The leukemic protein core binding factor beta (CBFbeta)-smooth-muscle myosin heavy chain sequesters CBFalpha2 into cytoskeletal filaments and aggregates. Mol Cell Biol 1998; 18: 7432–7443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kamikubo Y, Hyde RK, Zhao L, Alemu L, Rivas C, Garrett LJ et al. The C-terminus of CBFbeta-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis. Blood 2013; 121: 638–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang L, D'Costa J, Kummalue T, Civin CI, Friedman AD . Identification of a region on the outer surface of the CBFbeta-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization. Oncogene 2006; 25: 7289–7296.

    Article  CAS  PubMed  Google Scholar 

  9. Kummalue T, Lou J, Friedman AD . Multimerization via its myosin domain facilitates nuclear localization and inhibition of core binding factor (CBF) activities by the CBFbeta-smooth muscle myosin heavy chain myeloid leukemia oncoprotein. Mol Cell Biol 2002; 22: 8278–8291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lutterbach B, Hou Y, Durst KL, Hiebert SW . The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor. Proc Natl Acad Sci USA 1999; 96: 12822–12827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liao Y, Smyth GK, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014; 30: 923–930.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank NHGRI transgenic mouse core (Elsa Escoba, Cece Rivas and Gene Elliot), Irene C Ginty from OLM, microarray core (Abdel G Elkahloun), microscopic core (Stephen Wincovitch), flow cytometry core (Stacy Anderson and Martha Kirby), Bioinformatics core (Niraj Trivedi) and NIH Intramural Sequencing Center for their help. The research was supported by Intramural Research Program of National Human Genome Research Institute, National Institutes of Health.

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  1. L Zhao

    Present address: 4Current address: Human Immunology Core, Perelman School of Medicine, University of Pennsylvania, 409C Stellar Chance Labs, 422 Curie Blvd., Philadelphia, PA 19104, USA.,

Authors and Affiliations

  1. Oncogenesis and Development Section, NHGRI, NIH, Bethesda, MD, USA

    L Zhao, H Alkadi, E M Kwon, T Zhen, J Lichtenberg, L Alemu & P P Liu

  2. Transgenic Mouse Core, NHGRI, NIH, Bethesda, MD, USA

    J Cheng

  3. Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A D Friedman

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Correspondence to L Zhao or P P Liu.

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Zhao, L., Alkadi, H., Kwon, E. et al. The C-terminal multimerization domain is essential for leukemia development by CBFβ-SMMHC in a mouse knockin model. Leukemia 31, 2841–2844 (2017). https://doi.org/10.1038/leu.2017.262

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