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: 10.43). 10/2006; 20(9):1496-510. DOI: 10.1038/sj.leu.2404302
Source: PubMed


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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    • "Interestingly, it was found that the MLL gene was overexpressed 2.5-fold in TLFCK when compared to clear cell and chromophobe RCC. MLL is a recurring translocation in hematologic malignancies including lymphoblastic lymphomas and leukemias and can be found in 8% of T-ALL cases [23]. FISH analysis on a formalin fixed paraffin embedded section of tumor from our patient failed to demonstrate translocations or amplifications of the MLL gene. "
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    ABSTRACT: Thyroid-like follicular carcinoma of the kidney (TLFCK) is a rare histological variant of renal cell carcinoma not currently included in the World Health Organization classification of renal tumors. Only 24 previous cases of TLFCK have been reported to date. We report a case of TLFCK in a 19-year-old woman with history of pediatric acute lymphoblastic leukemia. This patient is the youngest with TLFCK to be reported to date and the first with history of lymphoblastic leukemia. The development of TLFCK in a young patient with history of lymphoblastic leukemia is interesting and suggests that genes involved in leukemogenesis may also be important for TLFCK pathogenesis. Recognition of TLFCK is important to distinguish it from other conditions that show thyroid-like features, as a misdiagnosis can result in adverse patient care.
    07/2014; 2014:313974. DOI:10.1155/2014/313974
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    • "Although activating mutations of NOTCH1 have been detected in 70% of both pediatric and adult T-ALL cases 3,10, significant age-related differences in the frequencies of other genetic alterations have been reported. For example, t(7;10)(q34;q24) and t(10;14)(q24;q11), both of which involve the translocation of the TCR in juxtaposition to the HOX11 transcription factor, occur in 7% of childhood T-ALL cases and 30% of adult T-ALL cases 16. Similarly, a higher prevalence of FBXW7 and PHF6 mutations was reported in adult T-ALL 10,17,18. "
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    ABSTRACT: Somatic mutations in cancer cell genes are classified according to their functional significance. Those that provide the malignant cells with significant advantage are collectively referred to as driver mutations and those that do not, are the passenger mutations. Accordingly, analytical criteria to distinguish driver mutations from passenger mutations have been recently suggested. Recent studies revealed mutations in interleukin-7 receptor-α (IL7R) gene in 10% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients and in only a few cases of pediatric B-ALL. IL7R mutations are also frequently found in patients with lung cancer, but whereas in pediatric T-ALL IL7R mutations are “drivers” (consisting of gain-of-function mutations within a narrow 50-base pair interval at exon 6 that confer cytokine-independent cell growth and promote tumor transformation), in lung cancer, mutations are substitution mutations randomly distributed across the gene and are probably only “passenger” events. Because the treatment response of adult T-ALL is significantly poorer than that of childhood T-ALL and because exon 6 IL7R mutations play a role in the pathogenesis of childhood T-ALL, we sought to determine how the pattern of IL7R mutations varies between adult and childhood T-ALL. To that end, we sequenced the 50-base pair interval in exon 6 of the IL7R of DNA obtained from bone marrow samples of 35 randomly selected adult patients with T-ALL. Our analysis revealed that none of these 35 samples carried an IL7R mutation in exon 6. Whether differences in the genetic makeup of adult and childhood T-ALL explain the differential response to therapy remains to be determined.
    Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.194 · 2.50 Impact Factor
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