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Acute lymphoblastic leukemia

Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo

Leukemia volume 29, pages 2307–2316 (2015)Cite this article

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Abstract

P38α/β has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, p38α/β also regulates other cellular processes. Here, we describe a role of p38α/β as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that p38α/β phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that p38α/β signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate p38α/β in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that p38α/β inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38α strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo p38α/β phosphorylation is associated with an inferior long-term relapse-free survival. We propose p38α/β as a mediator of proliferation and survival in ALL and show first preclinical evidence for p38α/β inhibition as an adjunct approach to conventional therapies.

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Acknowledgements

DMS and SL are supported by the Max-Eder group leader program by the Deutsche Krebshilfe e. V. DMS is supported by the Translational Research Training in Hematology Program 2014 by EHA and ASH. SL is further supported by the Deutsche Forschungsgemeinschaft (DFG), the Roggenbruck Stiftung, the Hamburger Krebsgesellschaft, the Medical Faculty of the University of Hamburg (FFM program) and the Hamburger Exzellenzinitiative (LEXI program). MC is supported by the Alexander von Humboldt Stiftung. IJ is supported by the Deutsche Forschungsgemeinschaft (SFB684, TP22) and the German José Carreras Leukemia Foundation (R10/26). JAA-G is supported by the Samuel Waxman Cancer Research Foundation Tumor Dormancy Program and NIH/National Cancer Institute grants (CA109182 and CA163131). We thank Katrin Timm-Richert, Katrin Neumann, Annika Brauer and Christian Bretscher for excellent technical assistance.

Author Contributions

DMS initiated, designed and supervised the research, analyzed the data and wrote the manuscript. SS and AA designed and performed experiments and analyzed the data. SK helped performing the experiments. CV performed the experiments and analyzed the data. MC and IJ contributed important constructs and professional expertise to the project. SL, GC, AT, JAA-G, M Stanulla and M Schrappe commented and discussed the research direction and edited the manuscript. All authors discussed the manuscript.

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Authors and Affiliations

  1. Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany

    A Alsadeq, S Strube, S Krause, G Cario, M Schrappe & D M Schewe

  2. Department of Gene Vectors, Helmholtz Zentrum München, Research Center for Environmental Health, Munich, Germany

    M Carlet & I Jeremias

  3. Department of Pediatric Pathology, Kiel Pediatric Tumor Registry, University of Kiel, Kiel, Germany

    C Vokuhl

  4. II. Medical Clinic and Institute of Tumor Biology, University Hospital Eppendorf, Hamburg, Germany,

    S Loges

  5. Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA

    J A Aguirre-Ghiso

  6. Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY, USA

    J A Aguirre-Ghiso

  7. Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany

    A Trauzold

  8. Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany

    M Stanulla

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  1. A Alsadeq
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Correspondence to D M Schewe.

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Alsadeq, A., Strube, S., Krause, S. et al. Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo. Leukemia 29, 2307–2316 (2015). https://doi.org/10.1038/leu.2015.153

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