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:10.1083/jcb1943oia8

Cited by 30 publications

(41 citation statements)

References 56 publications

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“…7F) (25, 33), suggesting elevated PDGFRβ expression is associated with a more aggressive form of T-ALL (34). Medyouf et al previously reported that IGF1R is a transcriptional target of NOTCH1 that is expressed on human T-ALL cells (35). Together, these findings reveal that elevated expression of PDGFRβ and IGF1R are shared characteristics of mouse and human T-ALL.…”

Section: Pdgfrβ and Igf1r Are Up-regulated On T-all Cells With Concomsupporting

confidence: 56%

“…IGF1 has been shown to directly support growth of solid and hematological malignancies (35,(39)(40)(41). To determine whether IGF1R signaling was required for DC-mediated T-ALL survival, we treated thymic and splenic T-ALL:DC cocultures with graded concentrations of three structurally distinct IGF1R inhibitors: AG-1024 (42), picropodophyllin (PPP) (43), and BMS-754807 (44).…”

Section: Activation Of the Mapk Pathway Is Associated With Igf1r Signmentioning

confidence: 99%

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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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Section: Pdgfrβ and Igf1r Are Up-regulated On T-all Cells With Concomsupporting

confidence: 56%

Section: Activation Of the Mapk Pathway Is Associated With Igf1r Signmentioning

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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“…84 Similar results were obtained by overexpressing IGF1R, which encodes insulin-like growth factor 1 receptor and is another NOTCH1 target ( Figure 2D). 88 In these cases, too, NOTCH-inhibiting therapies may be more effective when combined with AKT inhibitors. Furthermore, enhanced AKT activity may limit leukemia sensitivity to steroid treatment, 89,90 one of the cornerstone drugs in the treatment of human T-ALL.…”

Section: Rd Mendes Et Almentioning

confidence: 99%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of developing T cells in the thymus. T-ALL is characterized by chromosomal rearrangements. These rearrangements can lead to the aberrant activation of oncogenic transcription factors by placing their genes under the control of promoters and/or enhancers of Tcell receptor genes, the BCL11B gene, or other genes; occasionally, these rearrangements can give rise to oncogenic fusion proteins. The activated oncogenic transcription factors include TAL1 and LMO2 (and related family members), TLX1, TLX3, NKX2-1, HOXA, and MEF2C; in addition, certain oncogenic fusion proteins can directly activate the HOXA or MEF2C genes.1,2 Oncogenic proteins facilitate the developmental arrest of pre-leukemic immature T cells. We previously proposed that these chromosomal rearrangements should be classified as type A aberrations, as they are generally considered to be the driving oncogenic event associated with unique expression profiles.2 Based upon their gene expression signatures, T-ALL can be classified into the following four major subtypes: ETP-ALL, TLX, proliferative, and TALLMO. [3][4][5] Maturation arrest induces a pre-leukemic condition in which additional mutations can give rise to T-ALL.1,2 These secondary mutations are not necessarily clonal events and are often selected during disease progression or post-treatment T he tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycoly sis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

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“…S8, S9). Interestingly, BCR-ABL-expressing B cells also expressed high levels of the oncogenic Notch target gene Igf1r, which has been shown to be required for proliferation and leukemic-initiating activity in T-ALL (Medyouf et al 2011;Witkowski et al 2015). Altogether, these 14 genes common to the Notch and BCR-ABL data sets were found to be involved in lymphocyte differentiation, cell division, phosphorylation of protein, and cell cycle progression (Fig.…”

Section: Finger 4 Of Ikaros Controls Gene Expression In a Stage-specimentioning

confidence: 91%

Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor

2015

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The DNA-binding protein Ikaros is a potent tumor suppressor and hematopoietic regulator. However, the mechanisms by which Ikaros functions remain poorly understood, due in part to its atypical DNA-binding properties and partnership with the poorly understood Mi-2/NuRD complex. In this study, we analyzed five sequential stages of thymocyte development in a mouse strain containing a targeted deletion of Ikaros zinc finger 4, which exhibits a select subset of abnormalities observed in Ikaros-null mice. By examining thymopoiesis in vivo and in vitro, diverse abnormalities were observed at each developmental stage. RNA sequencing revealed that each stage is characterized by the misregulation of a limited number of genes, with a strong preference for stage-specific rather than lineagespecific genes. Strikingly, individual genes rarely exhibited Ikaros dependence at all stages. Instead, a consistent feature of the aberrantly expressed genes was a reduced magnitude of expression level change during developmental transitions. These results, combined with analyses of the interplay between Ikaros loss of function and Notch signaling, suggest that Ikaros may not be a conventional activator or repressor of defined sets of genes. Instead, a primary function may be to sharpen the dynamic range of gene expression changes during developmental transitions via atypical molecular mechanisms that remain undefined.

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

Cited by 30 publications

References 56 publications

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

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

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor

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