Molecular pathogenesis of T-cell leukaemia and lymphoma.

Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Nature Reviews Immunology 06/2008; 8(5):380-90. 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.

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    ABSTRACT: Background Kruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner. However, the roles of KLF4 in hematological malignancies and the mechanisms of action are not fully understood.Methods Inducible KLF4-overexpression Jurkat cell line combined with mouse models bearing cell-derived xenografts and primary T-cell acute lymphoblastic leukemia (T-ALL) cells from four patients were used to assess the functional role of KLF4 in T-ALL cells in vitro and in vivo. A genome-wide RNA-seq analysis was conducted to identify genes regulated by KLF4 in T-ALL cells. Chromatin immunoprecipitation (ChIP) PCR was used to determine direct binding sites of KLF4 in T-ALL cells.ResultsHere we reveal that KLF4 induced apoptosis through the BCL2/BCLXL pathway in human T-ALL cell lines and primary T-ALL specimens. In consistence, mice engrafted with KLF4-overexpressing T-ALL cells exhibited prolonged survival. Interestingly, the KLF4-induced apoptosis in T-ALL cells was compromised in xenografts but the invasion capacity of KLF4-expressing T-ALL cells to hosts was dramatically dampened. We found that KLF4 overexpression inhibited T cell-associated genes including NOTCH1, BCL11B, GATA3, and TCF7. Further mechanistic studies revealed that KLF4 directly bound to the promoters of NOTCH1, BCL2, and CXCR4 and suppressed their expression. Additionally, KLF4 induced SUMOylation and degradation of BCL11B.Conclusions These results suggest that KLF4 as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression.
    Molecular Cancer 02/2015; 14(1):26. DOI:10.1186/s12943-014-0285-x · 5.40 Impact Factor
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    ABSTRACT: T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting " leukemogenic " signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.
    BioMed Research International 09/2014; · 2.71 Impact Factor
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    ABSTRACT: Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer and an important cause of morbidity from haematological malignancies in adults. In the past several years, we have witnessed major advances in the understanding of the genetic basis of ALL. Genome-wide profiling studies, including microarray analysis and genome sequencing, have helped identify multiple key cellular pathways that are frequently mutated in ALL such as lymphoid development, tumour suppression, cytokine receptors, kinase and Ras signalling, and chromatin remodeling. These studies have characterized new subtypes of ALL, notably Philadelphia chromosome-like ALL, which is a high-risk subtype characterized by a diverse range of alterations that activate cytokine receptors or tyrosine kinases amenable to inhibition with approved tyrosine kinase inhibitors. Genomic profiling has also enabled the identification of inherited genetic variants of ALL that influence the risk of leukaemia development, and characterization of the relationship between genetic variants, clonal heterogeneity and the risk of relapse. Many of these findings are of direct clinical relevance and ongoing studies implementing clinical sequencing in leukaemia diagnosis and management have great potential to improve the outcome of patients with high-risk ALL.
    Nature Reviews Clinical Oncology 03/2015; DOI:10.1038/nrclinonc.2015.38 · 15.70 Impact Factor


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