IL-7 Contributes to the Progression of Human T-cell Acute Lymphoblastic Leukemias

Silva, Ana; Laranjeira, Angelo Brunelli Albertoni; Martins, Leila R.; Cardoso, Bruno; Demengeot, Jocelyne; Yunes, José Andrés; Seddon, Benedict; Barata, João T.

doi:10.1158/0008-5472.can-10-3606

Cited by 128 publications

(119 citation statements)

References 44 publications

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“…Most prior studies have focused on signaling via IL-7 (Dibirdik et al, 1991;Barata et al, 2004aBarata et al, ,b,c, 2005González-Garcia et al, 2009;Shochat et al, 2011;Silva et al, 2011) or mutational activation of intermediates in the PI3K-Akt pathway Gutierrez et al, 2009). The importance of PI3K-Akt activation in T-ALL is underscored by multiple studies showing that PI3K-Akt/mTOR inhibitors block growth/survival of T-ALL cells (Avellino et al, 2005;Wei et al, 2006;Palomero et al, 2007;Chiarini et al, 2009;Cullion et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…Although previous works have focused on the role of IL-7 signaling in T-ALL, including effects on downstream PI3K-Akt activation (Dibirdik et al, 1991;Barata et al, 2004aBarata et al, ,b,c, 2005González-Garcia et al, 2009;Shochat et al, 2011;Silva et al, 2011), we considered that insulin-like growth factor (IGF)-1 receptor (IGF1R) may also play an important role. IGFs and their receptors regulate normal cell growth and contribute to transformation and growth of malignant cells in many contexts (Pollak et al, 2004).…”

Section: Pharmacologic Inhibition Of Igf1r Compromises T-all Cell Growthmentioning

confidence: 99%

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High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

Medyouf¹,

Gusscott²,

Wang³

et al. 2011

J Cell Biol

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Section: Methodsmentioning

confidence: 99%

Section: Pharmacologic Inhibition Of Igf1r Compromises T-all Cell Growthmentioning

confidence: 99%

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

Medyouf¹,

Gusscott²,

Wang³

et al. 2011

J Cell Biol

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“…Thymocyte:TEC crosstalk is essential at multiple stages of T-cell development. TECs express NOTCH ligands and IL-7, which are required for differentiation of normal T-cells (13)(14)(15), but have also been implicated in T-ALL tumorigenesis (10,16). Thus, nascent lymphoma cells may coopt signals in the thymic microenvironment to promote tumor growth.…”

mentioning

confidence: 99%

“…Thus, nascent lymphoma cells may coopt signals in the thymic microenvironment to promote tumor growth. Previous studies demonstrated that stromal support is required for ex vivo survival of mouse and human T-ALL cells (10,(17)(18)(19)(20) and implicated IL-7 and NOTCH1 signaling in promoting tumor survival (10,(16)(17)(18). Together, these findings suggest that TECs might promote T-ALL.…”

mentioning

confidence: 99%

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

Triplett

Cardenas

Lancaster

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.

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“…IL-7 binds to a receptor (IL-7R) that is composed of cluster of differentiation (CD) 127 (IL-7Rα) and CD132 (γc), which is found on lymphoid progenitor cells, BCP cells and T cells. It has been demonstrated that IL-7 facilitates the proliferation and survival of leukemia cells (8)(9)(10), contributes to the progression and relapse of leukemia (11,12) and induces resistance to chemotoxins (13), thus contributing to the pathogenesis of ALL. As a result, identifying the leukemia-specific mediators of these IL-7-driven effects may enable the therapeutic targeting of this pathway.…”

Section: Introductionmentioning

confidence: 99%

Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia

et al. 2016

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Abstract. Y-box-binding protein 1 (YB-1) is a regulatory protein that is associated with drug resistance and relapse in solid tumors. As YB-1 mediates some of its activity through growth factor receptor signaling dysregulation, the present study compared the expression of YB-1 and interleukin 7 (IL-7) receptor α (IL-7Rα) in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and normal BCP cells. The expression levels of IL-7Rα and YB-1 were higher in relapsed vs. diagnostic samples of primary BCP ALL; however, co-expression was also observed in a minor BCP cell population in samples from healthy donors. Functional crosstalk between YB-1 and IL-7R was detected: Overexpression of YB-1 increased surface levels of IL-7R in B cells, and the stimulation of BCP ALL cell lines and primary samples by IL-7 activated YB-1 by phosphorylation at S102 in a phosphatidylinositol 3-kinase-independent and MEK1/2-dependent manner. Targeted knockdown of YB-1 reduced IL-7-mediated protection against rapamycin, and an inhibitor of MEK1/2 potentiated rapamycin-mediated killing in the presence of IL-7. These data establish a novel link between two well-characterized pro-survival factors in acute leukemia, and suggest that YB-1 inhibition may represent a novel therapeutic strategy for increasing sensitivity to chemotherapy in patients with refractory acute B-cell leukemia.

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IL-7 Contributes to the Progression of Human T-cell Acute Lymphoblastic Leukemias

Abstract: The importance of microenvironmental factors for driving progression in leukemia has been debated.

Cited by 128 publications

References 44 publications

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia

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