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Chronic myelogenous leukemia

A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia

Leukemia volume 29, pages 1668–1675 (2015)Cite this article

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Abstract

Targeted therapy of chronic myeloid leukemia (CML) is currently based on small-molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CCmut3, which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CCmut3 exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CCmut3 inhibits colony formation by primary CML CD34+ cells ex vivo, including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies.

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Acknowledgements

We are supported by the National Institutes of Health (Grants HL082978-01, CA04963920A2 and 1R01CA178397 to MWD and Grant CA129528 to CSL) and by the Leukemia and Lymphoma Society (Grant 7036-01 to MWD). MWD was supported, in part, by a clinical research scholarship of the Leukemia and Lymphoma Society. DWW was supported, in part, by a grant to the University of Utah from the Howard Hughes Medical Institute through the Med into Grad Initiative, and by the Graduate Research Fellowship from the University of Utah. AME is currently a scholar of the American Society of Hematology. We acknowledge the use of DNA/Peptide Core and Flow Cytometry Core (NCI Cancer Center Support Grant P30 CA042014, Huntsman Cancer Institute, Salt Lake City, UT, USA). We acknowledge support of funds in conjunction with Grant P30 CA042014 awarded to the Huntsman Cancer Institute. We also thank Karina Matissek and Abood Okal for technical assistance and useful scientific discussions.

Author Contributions

DWW designed and performed the research, collected data, analyzed and interpreted data and wrote the manuscript; AME assisted with patient sample experiments and virus preparation, provided key guidance in experimental design and wrote the manuscript. DWW and AME contributed equally. BJB and GDM assisted with cell line experiments; MSZ generated the Ba/F3 cell lines and assisted with preparation of figures; KRR processed patient samples; TO provided T315I patient samples and edited the manuscript; MWD supported the research on patient samples and cell lines and edited the manuscript; CSL provided key guidance in experimental design and support, and edited the manuscript.

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  1. D W Woessner

    Present address: 5Current address: Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA.,

  2. A M Eiring: Co-first author.

  3. M W Deininger and C S Lim: Co-senior author.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA

    D W Woessner

  2. Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA

    A M Eiring, M S Zabriskie, K R Reynolds, T O'Hare, M W Deininger & C S Lim

  3. Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, UT, USA

    B J Bruno, G D Miller & C S Lim

  4. Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA

    T O'Hare & M W Deininger

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Woessner, D., Eiring, A., Bruno, B. et al. A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia. Leukemia 29, 1668–1675 (2015). https://doi.org/10.1038/leu.2015.53

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