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Targeting Mature T Cell Leukemia

New Understanding of Molecular Pathways

  • Genomics In Human Disease
  • Published:
American Journal of Pharmacogenomics

Abstract

The best studied T cell leukemia/lymphoma from a genetic and biochemical point of view is T-cell chronic lymphocytic/prolymphocytic leukemia (T-CLL/T-PLL). This neoplasia commonly shows chromosomal rearrangements at 14q32.1 including translocations [t(14;14)(q11;q32), t(7;14)(q35;q32)], and inversions [inv(14)(q11;q32)]. The investigation of the locus in question at 14q32.1 resulted in the identification of two related genes named T cell leukemia/lymphoma 1 (TCL1) and TCL1b. Both genes are activated in T-CLL/T-PLL by the chromosomal aberrations mentioned above. Mice from a transgenic mouse strain expressing the TCL1 gene under the thymocyte specific lck promoter developed a mature T cell leukemia late in life, thereby demonstrating that over-expression of TCL1 induces the neoplastic transformation of T cells.

Biochemically, Tcl1 protein works as a co-factor of the Akt kinase, a key regulator of antiapoptotic and proliferative signals. Tcl1 interacts physically with Akt, increases its kinase activity and facilitates its transport to the nucleus. The pathogenesis of T-CLL/T-PLL may also involve Nur77, a T cell transcription factor required for T cell receptor-mediated apoptosis. Akt phosphorylates Nur77, thereby blocking its DNA-binding ability and rendering the transcription factor inactive.

The recently emerged insights into the molecular mechanisms of T cell leukemogenesis will allow for the development of specific pharmacological tools for the treatment of these hematopoietic malignancies.

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Acknowledgements

Supported by Kimmel Scholar Award and Special Fellowship of Leukemia and Lymphoma Society to Dr Pekarsky. ## The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th St, BLSB 1032, Philadelphia, Pennsylvania, 19107, USA

    Yuri Pekarsky, Cora Hollas & Carlo M. Croce

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  1. Yuri Pekarsky
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  2. Cora Hollas
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  3. Carlo M. Croce
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Correspondence to Yuri Pekarsky.

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Pekarsky, Y., Hollas, C. & Croce, C.M. Targeting Mature T Cell Leukemia. Am J Pharmacogenomics 3, 31–36 (2003). https://doi.org/10.2165/00129785-200303010-00005

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  • DOI: https://doi.org/10.2165/00129785-200303010-00005

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