Molecular basis of mature T-cell leukemia.
T-cell chronic lymphocytic/prolymphocytic leukemia (T-CLL/T-PLL) is a lymphoproliferative disease derived from immunocompetent post-thymic T cells. Activation (initiation of expression) of the TCL1 locus at chromosome 14q32.1 appears to be the causal event in the pathogenesis of these mature T-cell leukemias. This activation occurs as a result of translocations or inversions that cause rearrangement of the TCL1 (T-cell leukemia/lymphoma 1) locus with regulatory elements of T-cell receptor genes. To describe the molecular events that take part in the leukemogenesis of mature T-cell leukemias, we reviewed the literature and our own data on the molecular basis of mature T-cell leukemia. This data search revealed that 4 genes have been identified at the TCL1 locus: TCL1, TCL1b, TNG1, and TNG2. The expression of these genes is substantially increased following rearrangements involving 14q32.1. Functional analysis of the Tcl1 protein revealed its involvement in an Akt (protein kinase B) prosurvival pathway through its interaction with the Akt kinase, which promotes translocation of Akt to the nucleus and increases Akt's enzymatic activity. The available data provide important insights into the molecular mechanisms of T-cell leukemogenesis that may lead to the development of new drugs for treatment of mature T-cell leukemia.
Pekarsky
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Kimmel Cancer Center, 233 S 10th St, BLSB Room 1050, Philadelphia, PA 19107, USA.
Hallas
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Croce
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D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D007446:Chromosome Inversion; D002883:Chromosomes, Human, Pair 14; D004268:DNA-Binding Proteins / Q000502:physiology; D015870:Gene Expression; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000502:physiology; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C090851:TCL1A protein, human; D014157:Transcription Factors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt