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Acute lymphoblastic leukemia

Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia

Leukemia volume 35, pages 3101–3112 (2021)Cite this article

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Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting. Therefore, the aim of this study was to identify effective combination treatments against CRLF2-rearranged Ph-like ALL, and to elucidate the underlying mechanisms of synergy. We carried out a series of high-throughput combination drug screenings and found that ruxolitinib exerted synergy with standard-of-care drugs used in the treatment of ALL. In addition, we investigated the molecular effects of ruxolitinib on Ph-like ALL by combining mass spectrometry phosphoproteomics with gene expression analysis. Based on these findings, we conducted preclinical in vivo drug testing and demonstrated that ruxolitinib enhanced the in vivo efficacy of an induction-type regimen consisting of vincristine, dexamethasone, and l-asparaginase in 2/3 CRLF2-rearranged Ph-like ALL xenografts. Overall, our findings support evaluating the addition of ruxolitinib to conventional induction regimens for the treatment of CRLF2-rearranged Ph-like ALL.

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Fig. 1: HTS of the Ph-like ALL cell line MHH-CALL-4 to identify synergistic drug combinations with ruxolitinib.
Fig. 2: Ruxolitinib-induced gene expression changes in MHH-CALL-4 cells.
Fig. 3: Mass spectrometry phosphoproteomics analysis of the effects of dexamethasone, ruxolitinib, and their combination on kinase signaling pathways.
Fig. 4: In vivo efficacy of ruxolitinib in combination with standard-of-care drugs against Ph-like ALL PDXs.

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Acknowledgements

This research was supported by the National Health and Medical Research Council of Australia (NHMRC Fellowships APP1059804 and APP1157871 to RBL, NHMRC Program Grant 1091261), the NSW Cancer Council (Program Grant PG16-01), the Steven Walter Children’s Cancer Foundation, and the National Cancer Institute (CA199222 and CA199000). Children’s Cancer Institute Australia for Medical Research is affiliated with the UNSW Sydney and the Sydney Children’s Hospitals Network.

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  1. These authors contributed equally: Julia W. Bӧhm, Keith C. S. Sia

Authors and Affiliations

  1. Children’s Cancer Institute, School of Women’s and Children’s Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia

    Julia W. Bӧhm, Keith C. S. Sia, Connor Jones, Kathryn Evans, Anna Mariana, Tim Failes, Chelsea Mayoh, Greg Arndt, Murray D. Norris, Michelle Haber, Glenn M. Marshall & Richard B. Lock

  2. School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia

    Ignatius Pang & Marc R. Wilkins

  3. Bioanalytical Mass Spectrometry Facility, UNSW Sydney, Sydney, NSW, Australia

    Ling Zhong & Mark J. Raftery

  4. Incyte Corporation, Wilmington, DE, USA

    Robert Landman & Robert Collins

  5. RTI International, Research Triangle Park, NC, USA

    Stephen W. Erickson

  6. Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia

    Glenn M. Marshall

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Contributions

Conception and design: JWB, KCSS, RBL. Development of methodology: JWB, KCSS, AM, LZ. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): JWB, KCSS, CJ, KE, AM, RL, RC. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): JWB, KCSS, IP, CM, AM, TF. Writing, review, and/or revision of the manuscript: JWB, KCSS, CM, MDN, MH, GMM, RBL. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): MDN, MH, GMM. Study supervision: GA, MJR, MRW, RBL.

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Correspondence to Richard B. Lock.

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RL and RC are employees of Incyte Corporation. No potential conflicts of interest were disclosed by the other authors.

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Bӧhm, J.W., Sia, K.C.S., Jones, C. et al. Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia. Leukemia 35, 3101–3112 (2021). https://doi.org/10.1038/s41375-021-01248-8

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