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    Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

    Access Status
    Fulltext not available
    Authors
    De Smedt, Renate
    Morscio, Julie
    Reunes, Lindy
    Roels, Juliette
    Bardelli, Valentina
    Lintermans, Beatrice
    Van Loocke, Wouter
    Almeida, Afonso
    Cheung, Laurence
    Kotecha, Rishi
    Mansour, Marc R
    Uyttebroeck, Anne
    Vandenberghe, Peter
    La Starza, Roberta
    Mecucci, Cristina
    Lammens, Tim
    Van Roy, Nadine
    De Moerloose, Barbara
    Barata, Joao T
    Taghon, Tom
    Goossens, Steven
    Van Vlierberghe, Pieter
    Date
    2020
    Type
    Journal Article
    
    Metadata
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    Citation
    De Smedt, R. and Morscio, J. and Reunes, L. and Roels, J. and Bardelli, V. and Lintermans, B. and Van Loocke, W. et al. 2020. Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma. Blood. 135 (19): pp. 1685-1695.
    Source Title
    Blood
    DOI
    10.1182/blood.2019003880
    ISSN
    0006-4971
    Faculty
    Faculty of Health Sciences
    School
    School of Pharmacy and Biomedical Sciences
    Funding and Sponsorship
    http://purl.org/au-research/grants/nhmrc/1142627
    URI
    http://hdl.handle.net/20.500.11937/79574
    Collection
    • Curtin Research Publications
    Abstract

    T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non-cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non-cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.

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