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

(2020) BLOOD. 135(19). p.1685-1695
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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 highdose 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 Moloneymurine leukemia 1 (PIM1) in CD1271 T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD1271 T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after shortterm 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 CD1271 T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD1271 T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.
Keywords
JAK/STAT PATHWAY INHIBITION, TRANSCRIPTIONAL REGULATION, SERINE/THREONINE KINASES, PROTEIN-KINASES, IL-7 RECEPTOR, MURINE, GROWTH, PHOSPHORYLATION, PROLIFERATION, PROMOTER

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MLA
De Smedt, Renate, et al. “Targeting Cytokine- and Therapy-Induced PIM1 Activation in Preclinical Models of T-Cell Acute Lymphoblastic Leukemia and Lymphoma.” BLOOD, vol. 135, no. 19, 2020, pp. 1685–95, doi:10.1182/blood.2019003880.
APA
De Smedt, R., Morscio, J., Reunes, L., Roels, J., Bardelli, V., Lintermans, B., … Van Vlierberghe, P. (2020). Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma. BLOOD, 135(19), 1685–1695. https://doi.org/10.1182/blood.2019003880
Chicago author-date
De Smedt, Renate, Julie Morscio, Lindy Reunes, Juliette Roels, Valentina Bardelli, Béatrice Lintermans, Wouter Van Loocke, et al. 2020. “Targeting Cytokine- and Therapy-Induced PIM1 Activation in Preclinical Models of T-Cell Acute Lymphoblastic Leukemia and Lymphoma.” BLOOD 135 (19): 1685–95. https://doi.org/10.1182/blood.2019003880.
Chicago author-date (all authors)
De Smedt, Renate, Julie Morscio, Lindy Reunes, Juliette Roels, Valentina Bardelli, Béatrice Lintermans, Wouter Van Loocke, Afonso Almeida, Laurence C. Cheung, Rishi S. Kotecha, Marc R. Mansour, Anne Uyttebroeck, Peter Vandenberghe, Roberta La Starza, Cristina Mecucci, Tim Lammens, Nadine Van Roy, Barbara De Moerloose, Joao T. Barata, Tom Taghon, Steven Goossens, and Pieter Van Vlierberghe. 2020. “Targeting Cytokine- and Therapy-Induced PIM1 Activation in Preclinical Models of T-Cell Acute Lymphoblastic Leukemia and Lymphoma.” BLOOD 135 (19): 1685–1695. doi:10.1182/blood.2019003880.
Vancouver
1.
De Smedt R, Morscio J, Reunes L, Roels J, Bardelli V, Lintermans B, et al. Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma. BLOOD. 2020;135(19):1685–95.
IEEE
[1]
R. De Smedt et al., “Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma,” BLOOD, vol. 135, no. 19, pp. 1685–1695, 2020.
@article{8662245,
  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 highdose 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 Moloneymurine leukemia 1 (PIM1) in CD1271 T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD1271 T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after shortterm 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 CD1271 T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD1271 T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.}},
  author       = {{De Smedt, Renate and Morscio, Julie and Reunes, Lindy and Roels, Juliette and Bardelli, Valentina and Lintermans, Béatrice and Van Loocke, Wouter and Almeida, Afonso and Cheung, Laurence C. and Kotecha, Rishi S. and Mansour, Marc R. and Uyttebroeck, Anne and Vandenberghe, Peter and La Starza, Roberta and Mecucci, Cristina and Lammens, Tim and Van Roy, Nadine and De Moerloose, Barbara and Barata, Joao T. and Taghon, Tom and Goossens, Steven and Van Vlierberghe, Pieter}},
  issn         = {{0006-4971}},
  journal      = {{BLOOD}},
  keywords     = {{JAK/STAT PATHWAY INHIBITION,TRANSCRIPTIONAL REGULATION,SERINE/THREONINE KINASES,PROTEIN-KINASES,IL-7 RECEPTOR,MURINE,GROWTH,PHOSPHORYLATION,PROLIFERATION,PROMOTER}},
  language     = {{eng}},
  number       = {{19}},
  pages        = {{1685--1695}},
  title        = {{Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma}},
  url          = {{http://dx.doi.org/10.1182/blood.2019003880}},
  volume       = {{135}},
  year         = {{2020}},
}

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