Article

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: 33.84). 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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    • "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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    • "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; 2013:210253. DOI:10.1155/2013/210253
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    • "Missense Mutations To test the function of FBXW7 mutations in vivo, we targeted the most common recurrent mutation, an arginine-to-cysteine change at position 465 (468 in the mouse) (Aifantis et al., 2008). Given that mice that harbor a similar germline mutation in Fbxw7 die perinatally because of defects in lung development (Davis et al., 2011), we generated mutant alleles that could be conditionally activated with the Cre-lox system. "
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    ABSTRACT: Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.
    Cell 06/2013; 153(7):1552-66. DOI:10.1016/j.cell.2013.05.041 · 33.12 Impact Factor
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