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Acute myeloid leukemia

Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia

Leukemia volume 31, pages 1278–1285 (2017)Cite this article

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Abstract

Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a ‘second hit’ to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well known in CBF-AML but also mutations in the CCND1 and CCND2 genes, which represent novel frequent molecular alterations in AML with t(8;21). Altogether, CCND1 (n=2) and CCND2 (n=8) mutations were detected in 10 (15%) patients with t(8;21) in our cohort. A single CCND2 mutation was also found in 1 (0.9%) patient with inv(16). In contrast, CCND1 and CCND2 mutations were detected in only 11 (0.77%) of 1426 non-CBF-AML patients. All CCND2 mutations cluster around the highly conserved amino-acid residue threonine 280 (Thr280). We show that Thr280Ala-mutated CCND2 leads to increased phosphorylation of the retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of AML cell lines. The identification of CCND1 and CCND2 mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease.

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Acknowledgements

We thank the patients who consented to participate in these clinical trials and the families who supported them; to Donna Bucci and the CALGB/Alliance Leukemia Tissue Bank at The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA for sample processing and storage services and Lisa J Sterling and Chris Finks for data management. This work was supported in part by the National Cancer Institute (grants CA101140, CA140158, CA180861, CA196171, CA016058, CA180821, CA180882 and CA077658), the Leukemia Clinical Research Foundation, the Warren D. Brown Foundation, the Pelotonia Fellowship Program (to A-K Eisfeld) and by an allocation of computing resources from The Ohio Supercomputer Center.

Author contributions

A-KE, JCB, KM and CDB contributed to the study design; A-KE, AdlC, JCB, SS, CJW, KM and CDB contributed to data interpretation, A-KE, KM, AdlC and CDB wrote the manuscript; A-KE and SO generated the libraries for the targeted sequencing approach; A-KE analyzed the sequencing data; CS, MB and CJW performed laboratory-based research; JSB and KWK performed the data processing; JK and DN performed statistical analysis; AJC, JCB, JEK, MRB, RMS, BLP, KM and CDB were involved directly or indirectly in the care of patients and/or sample procurement. All authors read and agreed on the final version of the manuscript.

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Author notes

  1. K Mrózek, J C Byrd and C D Bloomfield: These authors contributed equally to this work.

Authors and Affiliations

  1. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    A-K Eisfeld, J Kohlschmidt, S Schwind, D Nicolet, C Shah, M Bainazar, K W Kroll, C J Walker, A de la Chapelle, K Mrózek & C D Bloomfield

  2. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    J Kohlschmidt & D Nicolet

  3. Division of Hematology, Department of Internal Medicine, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA

    J S Blachly, S Orwick & J C Byrd

  4. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    A J Carroll

  5. Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA

    B L Powell

  6. Dana-Farber/Partners CancerCare, Boston, MA, USA

    R M Stone

  7. Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY, USA

    J E Kolitz

  8. Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA

    M R Baer

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  1. A-K Eisfeld
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Correspondence to A-K Eisfeld, K Mrózek or C D Bloomfield.

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Eisfeld, AK., Kohlschmidt, J., Schwind, S. et al. Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31, 1278–1285 (2017). https://doi.org/10.1038/leu.2016.332

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