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Acute lymphoblastic leukemia

Preclinical efficacy of gemcitabine in MLL-rearranged infant acute lymphoblastic leukemia

Leukemia volume 34, pages 2898–2902 (2020)Cite this article

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The treatment of children diagnosed with acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, with 5-year event-free survival (EFS) approaching 85% [1]. However, 5-year EFS for infants diagnosed at less than 1 year of age with MLL-rearranged ALL remains less than 40% [2]. MLL-rearranged infant ALL is both clinically and biologically distinct from other childhood ALL subtypes, which is reflected by a unique gene expression profile [3], a remarkably silent mutational landscape [4], and pronounced resistance to currently applied chemotherapeutics [5].

To validate the results of our nucleoside analog drug screen, expanded dose-response curves were generated (Supplementary methods) for gemcitabine, floxuridine, cytarabine, and cladribine in five MLL-rearranged ALL cell lines (Fig. 1b–e). These experiments confirmed complete elimination of the leukemic cells at a concentration of 1000 nM in all cell lines tested, with IC50 values of less than 50 nM. Moreover, these data show that the dose-response curves for gemcitabine and floxuridine (Fig. 1b, c) are highly comparable to those of cytarabine and cladribine (Fig. 1d, e).

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Fig. 1: In vitro cytotoxicity screen and validation of nucleoside and nucleobase analog drugs on primary MLL-rearranged infant ALL cells and MLL-rearranged ALL cell lines.
Fig. 2: Gemcitabine is effective against infant ALL PDX models in vivo, in contrast to floxuridine.

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Acknowledgements

RSK is supported by a Fellowship from the National Health and Medical Research Council of Australia (NHMRC APP1142627). RSK and LCC are supported by the Children’s Leukaemia and Cancer Research Foundation (CLCRF, Australia).

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Author notes

  1. These authors contributed equally: Rishi S. Kotecha, Ronald W. Stam

Authors and Affiliations

  1. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Priscilla Wander, Sandra S. Pinhanҫos, Luke Jones, Susan T.C.J.M. Arentsen-Peters, Patricia Garrido Castro, Pauline Schneider, M. Emmy M. Dolman, Bianca Koopmans, Jan J. Molenaar, Rob Pieters, C. Michel Zwaan & Ronald W. Stam

  2. Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Priscilla Wander, Mark Kerstjens & C. Michel Zwaan

  3. Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia

    Laurence C. Cheung, Sajla Singh, Grace-Alyssa Chua & Rishi S. Kotecha

  4. School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA, Australia

    Laurence C. Cheung & Rishi S. Kotecha

  5. CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal

    Sandra S. Pinhanҫos

  6. Department of Haematology and Oncology, Perth Children’s Hospital, Perth, WA, Australia

    Rishi S. Kotecha

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  1. Priscilla Wander
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Contributions

PW, RWS, RSK, and LCC designed the study; RWS, RSK, LCC, CMZ, and JJM contributed materials; PW, SMP, RSK, LCC, SS, GAC, STCJMA, MK, MEMD, and BK performed the experiments; PW, SMP, RSK, LCC, SS, GAC, RWS, PS, and LJ analyzed data; RSK, LCC, and PW performed statistical analysis; PW and RWS wrote the paper; PW, RWS, RSK, CMZ, LJ, PGC, and RP supervised the study; and all co-authors performed critical review of the paper and gave their final approval.

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Correspondence to Rishi S. Kotecha or Ronald W. Stam.

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Wander, P., Cheung, L.C., Pinhanҫos, S.S. et al. Preclinical efficacy of gemcitabine in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia 34, 2898–2902 (2020). https://doi.org/10.1038/s41375-020-0895-9

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