Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: From thymocyte to lymphoblast

Department of Hematology, Cliniques Universitaires St Luc, Catholic University of Louvain, Brussels, Belgium.
Leukemia (Impact Factor: 9.38). 10/2006; 20(9):1496-510. DOI: 10.1038/sj.leu.2404302
Source: PubMed

ABSTRACT For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. Investigations are still very much actual, fed by the discovery of new genetic aberrations. In this review, we present a summary of the current cytogenetic changes associated with T-ALL. The genes deregulated by translocations or mutations appear to encode proteins that are also implicated in T-cell development, which prompted us to review the 'normal' and 'leukemogenic' functions of these transcription regulators. To conclude, we show that the paradigm of multistep leukemogenesis is very much applicable to T-ALL and that the different genetic insults collaborate to maintain self-renewal capacity, and induce proliferation and differentiation arrest of T-lymphoblasts. They also open perspectives for targeted therapies.

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Available from: Anne Hagemeijer, Mar 17, 2014
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    • "Ras proteins play a critical role in the transmission of survival signals from the cell membrane receptors to the intracellular transduction pathways. Mutations of RAS genes are common and have been described in various malignancies including acute leukemias [2]. They lead to the constitutive activation of the RAS-MAPK signaling cascade. "
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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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    • "cytometry, cytogenetics, fluorescence in situ hybridization, and molecular-genetic methods [8]. Although chromosomal rearrangements are common to T-ALL, there is still a large fraction of incidents (50%) where normal karyotype is seen [1]. The precise diagnosis of a tumor type is the most significant step in cancer treatments [9]. "
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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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    • "Approximately 90% of childhood Ph+ B- ALL cases express p190. The Ph in B-ALL—at least in childhood cases appears to arise in lymphoid lineage precursors, consistent with the notion that distinct target cells and BCR-ABL isoforms dictate the leukemia subtype that ultimately forms [128].Approximately one fourth of patients with pre–B-cell ALL have a t (1; 19) (q23; p13) translocation, which fuses the E2A gene on chromosome 19 with the PBX1 gene on chromosome 1.19. Paradoxically, the chimeric transcription factor induces both proliferation and apoptosis of lymphoid cells in transgenic mice [129] [130] [206]. "
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    ABSTRACT: Hematopoietic homeostasis is maintained throughout the lifetime of an individual through self-renewal of hematopoietic stem cells. Defects in the self -renewal and differentiation lead to hematopoietic insufficiency and development of malignancies. Leukemic stem cells (LSCs), which are considered to originate from hematopoietic stem or progenitor cells, not only adopt the regulatory machinery operating in normal HSCs but establish their own mechanisms against apoptosis and senescence. Hematopoietic malignancies are of Lymphoid origin with CLL and ALL and myeloid malignancies with AML and CML and in addition there are disease of the plasma multiple myelomas. One of the major therapeutic strategies for hematological malignancies is hematopoietic stem cell transplantation along with combination of chemotherapy. The review gives an insight of different hematological malignancies, the mechanism and therapeutic strategies available at present.
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