Molecular pathogenesis of T-cell leukaemia and lymphoma

ArticleinNature Reviews Immunology 8(5):380-90 · June 2008with29 Reads
DOI: 10.1038/nri2304 · Source: PubMed
Abstract
T-cell acute lymphoblastic leukaemia (T-ALL) is induced by the transformation of T-cell progenitors and mainly occurs in children and adolescents. Although treatment outcome in patients with T-ALL has improved in recent years, patients with relapsed disease continue to have a poor prognosis. It is therefore important to understand the molecular pathways that control both the induction of transformation and the treatment of relapsed disease. In this Review, we focus on the molecular mechanisms responsible for disease induction and maintenance. We also compare the physiological progression of T-cell differentiation with T-cell transformation, highlighting the close relationship between these two processes. Finally, we discuss potential new therapies that target oncogenic pathways in T-ALL.
    • "T-ALL is known by its clinical and biological characteristics and is generally associated with more unfavorable clinical features such as bone marrow infiltration, leukocytosis, mediastinal enlargement and central nervous system (CNS) damage. Although treatment outcome in patients with T-ALL has improved in recent years, the majority of patients still relapse during the long term follow-up [19][20][21]. In previous publications, researchers evaluated the effects of extracellular acidic pH on solid tumors, including breast, ovarian and prostate cancer, in vitro and in vivo. "
    [Show abstract] [Hide abstract] ABSTRACT: Some studies have shown that extracellular pH in tumors, which results in tumor progression, is less than that in normal tissues. The aim of this study was to investigate the effects of extracellular acidic pH on proliferation, invasion, and drug-induced apoptosis in acute lymphoblastic cells. The cells were cultured in different pH (pH 6.6 and pH 7.4) for 12 days. Cell proliferation was assessed by MTT assay and cell invasion was assayed by invasion assay and gene expression analysis of MMP-9. Drug-induced apoptosis was evaluated after exposure to doxorubicin for 24 hours by annexin V/PI staining and gene expression analysis of BAX pro-apoptotic protein. The results indicated the enhanced growth and invasion of leukemic cells at pH 6.6 (P ≤ 0.05). Furthermore, the cells at pH 6.6 were resistant to apoptosis by doxorubicin (P ≤ 0.05). It can be concluded that acidic pH increases the proliferation, invasion and reduces the drug-induced apoptosis in acute lymphoblastic leukemia. Extracellular acidity can influence the behavior of leukemic cells and therefore, the manipulation of extracellular liquid can be selected as a therapeutic strategy for leukemia, especially for acute lymphoblastic leukemia.
    Full-text · Article · Jul 2016
    • "Progress in T-ALL therapy has been impressive, with cure rates approaching 80% for children and 50% for adults [1, 2], however only limited therapeutic options are available for patients with primary resistant or relapsed disease. T-ALL is classiied into subgroups based on exclusive genetic alterations and/or deregulated expression of speciic transcription factors, including the TALL1/2, LMO1/2, TLX1/3 and HOXA families, associated with distinct stages of differentiation arrest [3][4][5]. Calcineurin (PPP3; PP2B referred to as Cn) is a calcium-activated serine/threonine (S/T) phosphatase, composed of a catalytic subunit (PPP3CA) and a regulatory subunit (PPP3CB), critical to a number of developmental processes in the cardiovascular, nervous, and immune system. Cn has the ability to dephosphorylate a broad range of proteins, including Nuclear Factor of Activated T cells (NFAT) proteins. "
    [Show abstract] [Hide abstract] ABSTRACT: Calcineurin (Cn) is a calcium activated protein phosphatase involved in many aspects of normal T cell physiology, however the role of Cn and/or its downstream targets in leukemogenesis are still ill-defined. In order to identify putative downstream targets/effectors involved in the pro-oncogenic activity of Cn in T-cell acute lymphoblastic leukemia (T-ALL) we used tandem affinity chromatography, followed by mass spectrometry to purify novel Cn-interacting partners. We found the Cn-interacting proteins to be part of numerous cellular signaling pathways including eIF2 signaling and mTOR signaling. Coherently, modulation of Cn activity in T-ALL cells determined alterations in the phosphorylation status of key molecules implicated in protein translation such as eIF-2α and ribosomal protein S6. Joint targeting of PI3K-mTOR, eIF-2α and 14-3-3 signaling pathways with Cn unveiled novel synergistic pro-apoptotic drug combinations. Further analysis disclosed that the synergistic interaction between PI3K-mTOR and Cn inhibitors was prevalently due to AKT inhibition. Finally, we showed that the synergistic pro-apoptotic response determined by jointly targeting AKT and Cn pathways was linked to down-modulation of key anti-apoptotic proteins including Mcl-1, Claspin and XIAP. In conclusion, we identify AKT inhibition as a novel promising drug combination to potentiate the pro-apoptotic effects of Cn inhibitors.
    Article · Jun 2016
    • "As a consequence, leukemia cells residing in the bone marrow depend upon AMPK more than those in the spleen to maintain metabolic homeostasis to glutamate for further processing in the TCA cycle [57]. Myc is a direct transcriptional target of Notch1 and supports Notch1-induced T-ALL pathogenesis58596061. A recent study using a Notch1 induced T-ALL model demonstrated that inhibition of Notch1 by gamma secretase inhibitor treatment attenuated glutaminolysis, making them reliant on autophagy to support metabolism and survival [62]. "
    [Show abstract] [Hide abstract] ABSTRACT: Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change cellular metabolism in a cell-intrinsic manner, priming cells for malignancy. Additionally, cell-extrinsic cues from the microenvironment, such as hypoxia, nutrient availability, oxidative stress, and crosstalk from surrounding cells can also affect cancer cell metabolism, and produce metabolic heterogeneity within the tumor. Here, we highlight recent findings revealing the complexity and adaptability of leukemia cells to coordinate metabolism.
    Article · Feb 2016
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