T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1

Zhu, Haichuan; Zhang, Liuzhen; Wu, Yilin; Dong, Bingjie; Guo, Weilong; Wang, Mei; Yang, Lu; Fan, Xiaoying; Tang, Yuqi; Liu, Ningshu; Lei, Xiaoguang; Wu, Hong

doi:10.7554/elife.38314

Cited by 36 publications

(54 citation statements)

References 70 publications

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“…Several findings also highlighted that Wnt/β-catenin signaling controls the earliest steps of healthy T-cell development, while its dysregulation may lead to malignant transformation of T-cell progenitors (Bigas, Guiu, & Gama-Norton, 2013;Guo et al, 2008;Zhu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological disorder that results from the clonal transformation of T‐cell precursors. Phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β‐catenin signaling pathways play a crucial role in T‐cell development and in self‐renewal of healthy and leukemic stem cells. Notably, β‐catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T‐ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β‐catenin pathway through ICG‐001, a CBP/β‐catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK‐474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T‐ALL cells. ICG‐001 and ZSTK‐474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β‐catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐ALL settings.

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Section: Discussionmentioning

confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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“…This observation suggests that Pten ablation is not responsible for maintaining LSC stemness features, once LICs have been generated. In this context, it is important to underline that recent findings have highlighted how self-renewal of T-ALL LICs is driven and maintained by β-catenin via a spleen focus-forming virus proviral integration oncogene 1 (SPI1)/hepatitis A virus cellular receptor 2 (HAVCR2) regulatory circuit [48] (see later on in this article). T-ALL LICs displayed a chromosomal translocation involving T-cell receptor α/δ and c-Myc ( Tcrα/δ-c-Myc ), which resulted in aberrant overexpression of the avian myelocytomatosis viral homolog (c-MYC) oncogene [44].…”

Section: Pten and T-all Development In Micementioning

confidence: 99%

The Key Roles of PTEN in T-Cell Acute Lymphoblastic Leukemia Development, Progression, and Therapeutic Response

Martelli

Paganelli

Fazio

et al. 2019

Cancers

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that comprises 10–15% of pediatric and ~25% of adult ALL cases. Although the curative rates have significantly improved over the past 10 years, especially in pediatric patients, T-ALL remains a challenge from a therapeutic point of view, due to the high number of early relapses that are for the most part resistant to further treatment. Considerable advances in the understanding of the genes, signaling networks, and mechanisms that play crucial roles in the pathobiology of T-ALL have led to the identification of the key drivers of the disease, thereby paving the way for new therapeutic approaches. PTEN is critical to prevent the malignant transformation of T-cells. However, its expression and functions are altered in human T-ALL. PTEN is frequently deleted or mutated, while PTEN protein is often phosphorylated and functionally inactivated by casein kinase 2. Different murine knockout models recapitulating the development of T-ALL have demonstrated that PTEN abnormalities are at the hub of an intricate oncogenic network sustaining and driving leukemia development by activating several signaling cascades associated with drug-resistance and poor outcome. These aspects and their possible therapeutic implications are highlighted in this review.

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“…Furthermore, homozygous PIK3CA H1047R hPSCs no longer require continuous PI3K pathway activation to sustain the enhanced stemness gene signature, consistent with their autocrine activation of TGFβ/NODAL signalling [99]. Evidence from bona fide cancer models of oncogenic PI3K pathway activation also suggests that the stemness phenotype can become uncoupled from the original trigger and thus no longer reversible simply through PI3K inhibition [99,135,136].…”

Section: A Note On Contextmentioning

confidence: 79%

“…One candidate worthy of further investigation is β-catenin due to its ability to activate transcription of NODAL, with NODAL subsequently sustaining its own expression through an autoregulatory positive feedback loop [137]. There is some evidence for an interaction between WNT/β-catenin and oncogenic PI3K pathway activation in promoting intestinal [30], mammary [138] and leukemic [135] stem cell maintenance, yet further studies will be required to determine the nature of this cross-talk and whether it operates in response to PIK3CA H1047R expression in hPSCs.…”

Section: A Note On Contextmentioning

confidence: 99%

PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.

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T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1

Cited by 36 publications

References 70 publications

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

The Key Roles of PTEN in T-Cell Acute Lymphoblastic Leukemia Development, Progression, and Therapeutic Response

PI3K in stemness regulation: from development to cancer

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