Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling

Giambra, Vincenzo; Jenkins, Catherine E.; Lam, Sonya H.L.; Hoofd, Catherine; Belmonte, Miriam; Wang, Xuehai; Gusscott, Sam; Gracias, Deanne; Weng, Andrew P.

doi:10.1182/blood-2014-10-609370

Cited by 106 publications

(104 citation statements)

References 49 publications

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“…Increasing evidence shows that common pathways regulate the self-renewal capacity in both normal and cancer stem cells and promote cancer progression when deregulated 24 . The most relevant examples include the Notch1, Wnt, and hypoxia-inducible factor (hif) cellular signalling pathways that modulate the maintenance and activity of lscs in t-all 16,19,22,25,26 . Interestingly, acquisition of mutations within those pathways contributes to leukemic progression by promoting selfrenewal and survival within supportive niches.…”

Section: Self-renewal Pathways Of Lsc Activitymentioning

confidence: 99%

“…Given the relevance of Wnt signalling in normal hematopoietic stem cells, the expectation is that, when deregulated, Wnt signalling might contribute to leukemia establishment and self-renewal activity by lscs 26,42,43 . Aberrant pathway activation leads to the malignant transformation of mouse hematopoietic cells and produces both chronic and acute myeloid leukemia 39 .…”

Section: Wnt Signalling Pathwaymentioning

confidence: 99%

“…Aberrant pathway activation leads to the malignant transformation of mouse hematopoietic cells and produces both chronic and acute myeloid leukemia 39 . In mouse thymocytes, constitutive stimulation of the pathway by transduction with active forms of β-catenin generates T-cell leukemia within 60-80 days 44 , and notably, lscs of mouse and human t-all are characterized by elevated levels of β-catenin protein 19,26 . In approximately 85% of human cases of t-all, abnormally high expression of β-catenin is observed at the protein level in non-leukemic thymocytes 45 .…”

Section: Wnt Signalling Pathwaymentioning

confidence: 99%

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Targeting Leukemia Stem Cells: Which Pathways Drive Self-Renewal Activity in T-Cell Acute Lymphoblastic Leukemia?

et al. 2016

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T-Cell acute lymphoblastic leukemia (t-all) is a malignancy of white blood cells, characterized by an uncontrolled accumulation of T-cell progenitors. During leukemic progression, immature T cells grow abnormally and crowd into the bone marrow, preventing it from making normal blood cells and spilling out into the bloodstream. Recent studies suggest that only discrete cell populations that possess the ability to recreate the entire tumour might be responsible for the initiation and propagation of t-all. Those unique cells are commonly called "cancer stem cells" or, in the case of hematopoietic malignancies, "leukemia stem cells" (lscs). Like normal hematopoietic stem cells, lscs are thought to be capable of self-renewal, during which, by asymmetrical division, they give rise to an identical copy of themselves as well as to a daughter cell that is no longer capable of self-renewal activity and represents a more "differentiated" progeny. Here, we review the main pathways of self-renewal activity in lscs, focusing on their involvement in the maintenance and development of t-all. New stem cell-directed therapies and lsc-targeted agents are also discussed.

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Section: Self-renewal Pathways Of Lsc Activitymentioning

confidence: 99%

Section: Wnt Signalling Pathwaymentioning

confidence: 99%

Section: Wnt Signalling Pathwaymentioning

confidence: 99%

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Targeting Leukemia Stem Cells: Which Pathways Drive Self-Renewal Activity in T-Cell Acute Lymphoblastic Leukemia?

et al. 2016

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“…A subset of LICs with active Wnt signaling has proven to reside preferentially within hypoxic niches in a mouse model of Notch-driven T-ALL. In particular, HIF1α upregulates the expression of β-catenin at the transcriptional level, which in turn potentiates Wnt signaling [55,56]. Targeting these key signaling cascades represents an attractive strategy.…”

Section: Breaking the Alliancementioning

confidence: 99%

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

Giacomo¹,

Fiore²,

Kyriakides³

et al. 2017

Clin Diagn Pathol

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T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy associated with a high risk of treatment failure. Efforts to improve outcomes have focused on underlying genetic defects. However, strong evidence suggests that leukemic cells prime a maladapted niche that in turn provides signals capable of sustaining the dormancy of leukemia initiating cells and protects them from toxic chemotherapeutic agents. Here, we aim to describe how key components of the bone marrow microenvironment are essential for leukemia initiation and progression. Although many mechanisms have been recently discovered, further studies are required to fully dissect the molecular mechanisms governing the bidirectional interactions between tumor and host cells. We predict that these new discoveries will pave the way for the implementation of novel therapeutic strategies and will eventually lead to the eradication of the drug-resistant cells, substantially and ultimately enhancing cure rates for T-ALL patients.

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“…However, (HIF1α). Up-regulates WNT signaling pathway under hypoxic condition in T-ALL, leading to WNT/β-catenin and HIF1 α support T-ALL cells [24]. Different strategy is developing targeting HIF1 α to exert hypoxia pro-survival effects of neoplastic cells [8].…”

Section: Hypoxiamentioning

confidence: 99%

Microenvironment and its role in acquire drug resistance of leukemia treatment

Qattan¹

2016

J Stem Cell Res Med

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Bone marrow niche is the microenvironment where the leukemic cells residue and it support cell proliferation, metastasis, and drug resistance by secretion of numerous factors including cytokines. When leukemic cells grow, they disrupt normal hematopoietic progenitor cell (HPC) bone marrow niches and create abnormal microenvironments. Also, niches recently have been linked to the development of drug resistance. One type of stem cell that resides in the bone marrow niche is called Mesenchymal stem cells (MSCs). Two microenvironment niches have been identified in BM; Osteoblastic and vascular, these niches provide the area in where the leukemia cells can escape from the chemotherapy-induced death and acquire drug resistance cells. Moreover, this review highlight briefly the role of exosomes in cell-to-cell communication and progression. The interaction between BM and leukemia cells through different proteins including cytokines, adhesion molecule, signal transduction pathways and hypoxia are mentioned simply.MSCs have potential successful uses in regenerative medicine, but in this short review focusing on their potential role in supporting resistance in leukemia and the progress in elucidating the cellular components of HSC in BM.

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Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling

Abstract: Key Points A real-time, integrated fluorescent Wnt reporter marks rare leukemia stem cells in T-ALL. Deletion of β-catenin or Hif1α reduces LIC frequency in established tumors, but does not affect the growth of bulk cells.

Cited by 106 publications

References 49 publications

Targeting Leukemia Stem Cells: Which Pathways Drive Self-Renewal Activity in T-Cell Acute Lymphoblastic Leukemia?

Targeting Leukemia Stem Cells: Which Pathways Drive Self-Renewal Activity in T-Cell Acute Lymphoblastic Leukemia?

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

Microenvironment and its role in acquire drug resistance of leukemia treatment

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