Targeting mature T cell leukemia: new understanding of molecular pathways

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.