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 (Impact Factor: 34.99). 06/2008; 8(5):380-90. DOI: 10.1038/nri2304
Source: PubMed


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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    • "They are not expressed in developing T cells but seem to be involved in spleen development. In leukemogenesis, they are the most frequent aberrantly expressed genes becoming active due to the translocation involving the TCR loci [1] [28]. TLX1 is expressed in 7% of children and in about 30% of adults with T-ALL, displaying an early cortical phenotype. "
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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; 2015. DOI:10.1155/2015/750203 · 2.71 Impact Factor
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    • "However, patients with several ALL subtypes continue to show a poor prognosis, and treatments are responsible for the short and long-term toxicities experienced by certain long-term surviving patients. Unfortunately, the majority of patients eventually experience relapse or succumb to their disease after developing drug resistance (30). However, monoclonal antibodies, gene inhibitors and upregulation of microRNAs (31–33) may provide promising tools in the search for ALL-targeted therapy. "
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    ABSTRACT: SLC25A38 is a recently identified protein that belongs to the mitochondrial solute carrier family, SLC25. Previous studies have shown that it is a pro-apoptotic protein, which regulates intrinsic caspase-dependent apoptosis. In order to clarify the effect of SLC25A38 protein expression on acute lymphoblastic leukemia (ALL) cells, we detected the expression of SLC25A38 in various cell lines (RPMI 8226, U266, Molt-4 and Jurkat) by western blot analysis. The results indicate that SLC25A38 is highly expressed in the four cell lines. Among 55 leukemia patients (adult, n=32 and infant, n=23), a high expression of SLC25A38 protein was observed in seven infant (7/23, 30.4%) and 15 adult (15/32, 46.9%) ALL patients. Two adult ALL patients that were positive for SLC25A38 were analyzed and the level of SLC25A38 significantly reduced or disappeared following combined chemotherapy, however, reappeared upon ALL recurrence. The expression level was identified to be associated with the proportion of blast cells in the bone marrow. Additionally, SLC25A38 and Notch1 were co-expressed in the four cell lines and the ALL patient samples. The present results show that expression of SLC25A38 is a common feature of ALL cells and may be a novel biomarker for diagnosis, as well as a potential therapeutic target for ALL.
    Oncology letters 05/2014; 7(5):1422-1426. DOI:10.3892/ol.2014.1947 · 1.55 Impact Factor
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    • "Translocations give rise to not only promoter exchange but also fusion genes, encoding chimeric proteins [1]. The other molecular-genetic abnormalities in T-ALL involve deletions , amplifications, and point mutations which activate oncogenes or inhibit tumor suppressors, which, in turn, cause differentiation arrest in thymocytes [1] [2] [3]. Deletions are the reason for loss of tumor suppressors. "
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    ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is a complex disease, resulting from proliferation of differentially arrested immature T cells. The molecular mechanisms and the genes involved in the generation of T-ALL remain largely undefined. In this study, we propose a set of genes to differentiate individuals with T-ALL from the nonleukemia/healthy ones and genes that are not differential themselves but interconnected with highly differentially expressed ones. We provide new suggestions for pathways involved in the cause of T-ALL and show that network-based classification techniques produce fewer genes with more meaningful and successful results than expression-based approaches. We have identified 19 significant subnetworks, containing 102 genes. The classification/prediction accuracies of subnetworks are considerably high, as high as 98%. Subnetworks contain 6 nondifferentially expressed genes, which could potentially participate in pathogenesis of T-ALL. Although these genes are not differential, they may serve as biomarkers if their loss/gain of function contributes to generation of T-ALL via SNPs. We conclude that transcription factors, zinc-ion-binding proteins, and tyrosine kinases are the important protein families to trigger T-ALL. These potential disease-causing genes in our subnetworks may serve as biomarkers, alternative to the traditional ones used for the diagnosis of T-ALL, and help understand the pathogenesis of the disease.
    07/2013; 2013(12):210253. DOI:10.1155/2013/210253
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