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

Medyouf, Hind; Gusscott, Samuel; Wang, Hongfang; Tseng, Jen-Chieh; Wai, Carol; Nemirovsky, Oksana; Trumpp, Andreas; Pflumio, Françoise; Carboni, Joan M.; Gottardis, Marco M.; Pollak, Michael; Kung, Andrew L.; Aster, Jon C.; Holzenberger, Martin; Weng, Andrew P.

doi:10.1084/jem.20110121

Cited by 154 publications

(120 citation statements)

References 66 publications

(96 reference statements)

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“…The important contribution of IGF-IR signaling to the survival of T-LBL has been recently documented [29]. In the present study, the significance of IGF-IR, as a potential molecular target in T-LBL, was stressed once again when PPP induced negative biological effects in Jurkat and Molt-3 cells.…”

Section: Discussionmentioning

confidence: 63%

“…Importantly, a recent study has supported major contributions of IGF-IR to the survival of leukemia-initiating cells in T-LBL. This study also concluded that IGF-IR inhibitors could have a major impact on the treatment of this aggressive type of cancer in the near future [29]. Because PPP is a potent, selective inhibitor of IGF-IR that is currently being explored in clinical trials of resistant cancer patients with notable success, we set out to examine the effects of PPP on prototype T-LBL cell lines including Jurkat and Molt-3.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma

Huang

Fang

Zhao

et al. 2014

Leukemia & Lymphoma

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It has been recently shown that IGF-IR contributes significantly to the survival of T lymphoblastic leukemia/lymphoma (T-LBL) cells, and it was therefore suggested that IGF-IR could represent a legitimate therapeutic target in this aggressive disease. Picropodphyllin (PPP) is a potent, selective inhibitor of IGF-IR that is currently used with notable success in clinical trials that include patients with aggressive types of epithelial tumors. In the present study, we tested the effects of PPP on Jurkat and Molt-3 cells; two prototype T-LBL cell lines. Our results demonstrate that PPP efficiently induced apoptotic cell death and cell cycle arrest of these two cells. These effects were attributable to alterations of downstream target proteins. By using proteomic analysis, 7 different proteins were found to be affected by PPP treatment of Jurkat cells. These proteins are involved in various aspects of cellular metabolism, cytoskeleton organization, and signal transduction pathways. The results suggest that PPP affects multiple signaling molecules and inhibits fundamental pathways that control cell growth and survival. Our study also provides novel evidence that PPP could be potentially utilized for the treatment of the aggressive T-LBL.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma

Huang

Fang

Zhao

et al. 2014

Leukemia & Lymphoma

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“…Importantly, the TSGs and oncogenes co-enriched with increased H3K79me2 and H3K36me3 in MA9 cells were included in the MA9-K79-K36- Setd2 -DEGs. The critical functions of these TSGs and oncogenes have been reported in leukemia patients 18–24 (Figures 2c and 4b, Supplementary Tables S1–S3). Moreover, pathway analysis showed that AML-related disease terms were significantly enriched in MA9-K79-K36- Setd2 -DEGs (Figure 4c), suggesting their functions in MLLr leukemogenesis.…”

Section: Resultsmentioning

confidence: 77%

SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia

Chen

Yan

et al. 2017

Leukemia

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Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusiontarget genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.

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“…Co-culture with ECs induced transcripts characteristic of LICs, including CD44, IGF1R and CSF1R (Hanahan and Weinberg, 2011; Medyouf et al, 2011) (Figure 1I, Table S1). Flow cytometry analysis and quantitative PCR (qPCR) confirmed that EC coculture-mediated upregulation of corresponding proteins was due to generation of a CD44 + IGF1R + CSF1R + LC subset (Figures 1J, S1F–G).…”

Section: Resultsmentioning

confidence: 99%

“…Notch signaling is a pivotal modulator of lymphomagenesis (Aster et al, 2008; Espinosa et al, 2010; Liu et al, 2010; Lobry et al, 2013), enhancing Myc activity and upregulating receptors such as IGF1R (Medyouf et al, 2011; Weng et al, 2006). The Jagged (Jag) and Delta-like (Dll) families of Notch ligands induce Notch signaling (Gridley, 2010; Siekmann and Lawson, 2007).…”

Section: Introductionmentioning

confidence: 99%

Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance

et al. 2014

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Summary Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is not understood how vascular niche-derived paracrine factors, known as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B-Cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch-ligand Jagged1 (Jag1) on neighboring tumor ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44+IGF1R+CSF1R+ LC phenotypes, including extra-nodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop could inhibit LC aggressiveness and enhance chemosensitivity.

show abstract

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

Abstract: Notch-driven expression of IGF1R promotes the growth, viability, and transplantability of T-ALL cells.

Cited by 154 publications

References 66 publications

Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma

Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma

SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia

Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance

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