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Special Communication |

Molecular Basis of Mature T-Cell Leukemia

Yuri Pekarsky, PhD; Cora Hallas, PhD; Carlo M. Croce, MD
JAMA. 2001;286(18):2308-2314. doi:10.1001/jama.286.18.2308.
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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 TCL1locus 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.

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Figure 1. Chromosomal Rearrangements at 14q32.1 in Human T-Cell Leukemias
Graphic Jump Location
From left to right, normal, translocation t(14;14)(q11;q32.1), and inversion inv(14)(q11;q32.1). Segments within boxes indicate chromosomal rearrangement. TCRα indicates T-cell receptor α gene; TCL1, T-cell leukemia/lymphoma 1 gene; TNG, TCL1 neighboring gene 1; and IgH, immunoglobulin heavy chain gene. indicates variable gene segment of TCRα; , joining segment; and , constant segment. The small D (diversity) segment (see text) is not pictured but is located upstream of the J segment. Arrows indicate orientation of transcription.
Figure 2. Human and Murine TCL1 Loci
Graphic Jump Location
A, human locus; B, mouse locus. This Figure illustrates more extensive cytogenetic data for the human locus than previous versions.19,20,29 For definition of terms, see legend for Figure 1. Vertical arrows represent positions of cloned 14q32.1 breakpoints in T-PLL/T-CLL cells. Restriction enzyme sites are shown for the following enzymes: BssHII (B), ClaI (C), EagI (E), KspI (K), MluI (M), NotI (N), NruI (R), SalI (S), and SfiI (F). Horizontal arrows indicate orientation of transcription.
Figure 3. The Role of Tcl1 in the Akt Oncogenic Pathway
Graphic Jump Location
Tcl1 binds to Akt1 kinase in cytoplasm through its pleckstrin homology domain and enhances the phosphorylation of Nur77 at serine 350 in its DNA binding domain. This phosphorylation occurs in the cytoplasm or possibly in the nucleus. Normally, Nur77 acts as a transcription factor, but, when phosphorylated, it cannot bind the DNA and therefore is inactive.

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