Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia

Gachet, Stéphanie; Genescà, Eulàlia; Passaro, Diana; Irigoyen, Marta; Alcalde, Hélène; Clémenson, Céline; Poglio, Sandrine; Pflumio, Françoise; Janin, Anne; Lasgi, Charlène; Dodier, Sophie; Soyer, Magali; Duménil, Gérard; Ghysdael, Jacques

doi:10.1038/leu.2013.156

Cited by 45 publications

(91 citation statements)

References 43 publications

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“…Calcineurin Inactivation Affects CXCR4 Surface Expression and CXCL12/CXCR4-Induced T-ALL Cell Migration T-ALL induced in mice by an activated allele of NOTCH1 (ICN1) were generated as previously described (Gachet et al, 2013). Infusion of these leukemias (ICN1;Rosa-Cre-ER T2 and carrying either the Ppp3r1 fl/fl , Ppp3r1 fl/+ , Ppp3r1 fl/À , or Ppp3r1 +/+ alleles) into secondary wild-type hosts resulted in their synchronous engraftment.…”

Section: Resultsmentioning

confidence: 99%

“…Calcineurin (PPP3) is a serine-threonine protein phosphatase that we previously showed to be activated in T-ALL (Medyouf et al, 2007) and identified as essential to LIC activity in T-ALL mouse models (Gachet et al, 2013;Medyouf et al, 2007). In somatic tissues, calcineurin is composed of a catalytic subunit, encoded by two distinct genes (PPP3CA and PPP3CB), and a regulatory subunit, encoded by PPP3R1.…”

Section: Introductionmentioning

confidence: 99%

“…In somatic tissues, calcineurin is composed of a catalytic subunit, encoded by two distinct genes (PPP3CA and PPP3CB), and a regulatory subunit, encoded by PPP3R1. Calcineurin regulates the physical and functional interaction that T-ALL cells establish with other cells in the tumor microenvironment, notably their adhesive and migratory properties (Gachet et al, 2013). Calcineurin-dependent adhesive and migratory properties may regulate the ability of leukemic cells to reach their supportive stromal niches, dynamically exchange between different niche compartments, and exit from these niches for further dissemination.…”

Section: Introductionmentioning

confidence: 99%

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CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia

et al. 2015

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Impaired cell migration has been demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cells upon calcineurin inactivation, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation, and ultimately inhibition of leukemia-initiating cell (LIC) activity. Herein we demonstrate that the chemokine receptor CXCR4 is essential to the LIC activity of T-ALL leukemic cells both in NOTCH-induced mouse T-ALL and human T-ALL xenograft models. We further demonstrate that calcineurin regulates CXCR4 cell-surface expression in a cortactin-dependent manner, a mechanism essential to the migratory properties of T-ALL cells. Because 20%-25% of pediatric and over 50% of adult patients with T-ALL do not achieve complete remission and relapse, our results call for clinical trials incorporating CXCR4 antagonists in T-ALL treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia

et al. 2015

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“…Notch1 exon sequencing revealed nonsynonymous mutations in the heterodimerization or PEST domains in 64% (9/14) of primary LN3 tumors, with premature STOP codons in the PEST domains of 42% (6/14) of LN3 T-ALLs (Table S1). Thus, T-ALL in the LN3 model shares characteristics with human NOTCH-driven cortical T-ALL, including constitutive NOTCH signaling and NFAT activation (Table S1) (19,21,22), as well as expression of CD8 with variable levels of CD4 (21), and elevated expression of the NOTCH1 transcriptional targets Hes1, Dtx1, and pTCRa (https://gexc.stanford. edu/models/1118/genes).…”

Section: Resultsmentioning

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.…”

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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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Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC

Wan

Zhang

et al. 2022

Molecular Oncology

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Although growth arrest‐specific protein 2 (GAS2) promotes the growth of T‐cell acute lymphoblastic leukemia (T‐ALL) cells in culture, the effect of GAS2 on T‐cell leukemogenesis has not been studied, and the mechanism remains unclear. In the present study, xenograft studies showed that GAS2 silencing impaired T‐cell leukemogenesis and decreased leukemic cell infiltration. Mechanistically, GAS2 regulated the protein expression of C‐X‐C chemokine receptor type 4 (CXCR4) rather than its transcript expression. Immunoprecipitation revealed that GAS2 interacted with CXCR4, and confocal analysis showed that GAS2 was partially co‐expressed with CXCR4, which provided a strong molecular basis for GAS2 to regulate CXCR4 expression. Importantly, CXCR4 overexpression alleviated the inhibitory effect of GAS2 silencing on the growth and migration of T‐ALL cells. Moreover, GAS2 or CXCR4 silencing inhibited the expression of NOTCH1 and c‐MYC. Forced expression of c‐MYC rescued the growth suppression induced by GAS2 or CXCR4 silencing. Meanwhile, GAS2 deficiency, specifically in blood cells, had a mild effect on normal hematopoiesis, including T‐cell development, and GAS2 silencing did not affect the growth of normal human CD3+ or CD34+ cells. Overall, our data indicate that GAS2 promotes T‐cell leukemogenesis through its interaction with CXCR4 to activate NOTCH1/c‐MYC, whereas impaired GAS2 expression has a mild effect on normal hematopoiesis. Therefore, our study suggests that targeting the GAS2/CXCR4 axis is a potential therapeutic strategy for T‐ALL.

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Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia

Cited by 45 publications

References 43 publications

CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia

CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia

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

Growth arrest‐specific protein 2 (GAS2) interacts with CXCR4 to promote T‐cell leukemogenesis partially via c‐MYC

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