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

De Smedt, R; Morscio, J; Reunes, L; Roels, J; Bardelli, V; Lintermans, B; Van Loocke, W; ... Van Vlierberghe, P; + view all (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. 10.1182/blood.2019003880. Green open access

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Abstract

T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are aggressive hematological malignancies that are currently treated with high dose chemotherapy. Over the last years, the search towards 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 IL7 can increase the expression of the oncogenic kinase 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 to bulk non-treated 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 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.

Type: Article
Title: Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood.2019003880
Publisher version: https://doi.org/10.1182/blood.2019003880
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: adult t-cell lymphoma/leukemia, cytokine, lymphoma, t-cell leukemia, acute, lymphoblastic t-cell lymphoma, interleukin 7 receptor, interleukin-7, chemotherapy, neoadjuvant, chemotherapy regimen, glucocorticoids
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10096543
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