Targeting Mature T Cell LeukemiaNew Understanding of Molecular Pathways
作者:
Yuri Pekarsky,
Cora Hallas,
Carlo M. Croce,
期刊:
American Journal of PharmacoGenomics
(ADIS Available online 2003)
卷期:
Volume 3,
issue 1
页码: 31-36
ISSN:1175-2203
年代: 2003
出版商: ADIS
关键词: Haematological malignancies;Lymphoid leukaemia;Non Hodgkin's lymphoma;Pharmacogenomics
数据来源: ADIS
摘要:
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) andTCL1b. Both genes are activated in T-CLL/T-PLL by the chromosomal aberrations mentioned above. Mice from a transgenic mouse strain expressing theTCL1gene under the thymocyte specificlckpromoter developed a mature T cell leukemia late in life, thereby demonstrating that over-expression ofTCL1induces 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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