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The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia

Leukemia volume 31, pages 2267–2271 (2017)Cite this article

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Chromosomal rearrangements involving the two subunits of the heterodimeric transcription factor, core-binding factor (CBF), are the most commonly observed cytogenetic abnormalities in adult acute myeloid leukemia (AML). CBF comprises one of three potential DNA-binding α-subunits (RUNX1, RUNX2 or RUNX3)1 that interact with a non-DNA-binding subunit, CBFβ. The major rearrangement affecting CBFβ generates the inv(16)(p13.1q22) that fuses the first 165 amino acids of CBFβ with the coiled-coil rod domain of the smooth muscle myosin heavy chain (SMMHC) gene, MYH11.2, 3 The resulting CBFβ–SMMHC fusion protein retains the ability to interact with RUNX1, and functions by dominantly inhibiting normal CBF activity. This view is supported by studies where CBFβ-MYH11 was knocked into the endogenous CBFβ locus, resulting in an early embryonic lethality that phenocopied many of the developmental abnormalities observed in mice with homozygous deletions of either RUNX1 or CBFβ.4, 5 CBFβ–SMMHC may dominantly inhibit CBF function by recruiting nuclear corepressor molecules, including mSin3A and HDAC8, to a C-terminal region of SMMHC that includes the 28-amino-acid assembly competence domain (ACD) that mediates skeletal or smooth muscle myosin oligomerization and filament formation.6, 7, 8, 9

Analysis of transplant recipients showed that mice reconstituted with CBFβ–SMMHC-expressing cells (CBFβ–SMMHC mice) died of AML between 4 and 7 months PT (Figure 1c). Disease penetrance was 100% when GFP+ cells exceeded 5% in peripheral blood (PB) at 3–4 weeks PT (GFP+ chimerism ranged between 5.7 and 11.6%, mean=9.1%, n=16). GFP+ chimerism in MIG control and ΔACD mice was stable over time (Figure 1d), with no MIG or ΔACD animal showing outward signs of sickness at least 12 months PT. The comparable expression levels of the ΔACD mutant and CBFβ–SMMHC indicated that this does not account for their differing potencies in promoting AML.

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Acknowledgements

We thank Dr John Roth (UC-Davis) for thoughtful discussions and Dr Yufeng Li for statistical help. We sincerely apologize to colleagues whose work we were not able to cite due to space limitations. This work was supported by the NIH consortium grant to SWH (2RO1CA087549-06), by NIH RO1CA096798 and R01CA144248 (to CAK), RO1HL089176 (to ADF) and P30CA013148 (to RAO and DC).

Author contributions

H-GK, CSS, HJN, JL, SP-G, CVC, RK and LG designed and performed the experiments; RAO and DC provided biostatistical analysis; VR analyzed histology results; SWH, ADF and CAK designed experiments; H-GK and CAK wrote the manuscript.

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Authors and Affiliations

  1. Department of Microbiology, University of Alabama-Birmingham, Birmingham, AL, USA

    H-G Kim, J LeGrand, C S Swindle, H J Nick, S Purohit-Ghelani, L Gartland & C A Klug

  2. Department of Medicine, University of Alabama-Birmingham, Birmingham, AL, USA

    R A Oster & D Chen

  3. Department of Pathology, University of Alabama-Birmingham, Birmingham, AL, USA

    C V Cotta, V Reddy & C A Klug

  4. Department of Biochemistry and Molecular Genetics, University of Alabama-Birmingham, Birmingham, AL, USA

    R Ko & C A Klug

  5. Department of Biochemistry, Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

    S W Hiebert

  6. Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA

    A D Friedman

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  1. H-G Kim
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Correspondence to C A Klug.

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Kim, HG., LeGrand, J., Swindle, C. et al. The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia. Leukemia 31, 2267–2271 (2017). https://doi.org/10.1038/leu.2017.236

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