Molecular Basis of Mature T-Cell Leukemia

Abstract

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.

Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL

“…Both aberrations are frequently found in mature post-thymic T-cell malignancies including T-prolymphocytic leukemia (T-PLL) and adult T-cell leukemia/lymphoma (ATLL). 23,24 The 14q32 band corresponds to a 18 Mb long DNA fragment containing approximately 200 genes. Therefore, cytogenetically similar aberrations might affect different genes.…”

“…In T-PLL both inv(14)(q11q32) and t(14;14)(q11;q32) result in a recombination between the TCRA/D locus and the T-cell leukemia/lymphoma (TCL) gene cluster containing TCL1, TCL1B, TNG1 and TNG2. 23 In contrast, in ATLL the involvement of either IGH or TCL genes was excluded in the majority of cases with 14q32 alterations. 25 To our knowledge, hardly any molecular breakpoint analyses have been performed on T-ALL inv(14)(q11q32) or t(14;14)(q11;q32).…”

T-cell lymphomas mask slower developing B-lymphoid and myeloid tumours in transgenic mice with broad haemopoietic expression of MYC

“…In humans, T-cell chronic lymphocytic leukaemia and T-cell prolymphocytic leukaemia are largely diseases of CD4 þ CD8 À T cells (Harris et al, 1994) and share further surface characteristics (TCRb þ CD3 þ CD5 þ CD2 þ CD25 À ) with the VavP-MYC17 tumours (Figure 3c). These leukaemias are associated with chromosomal rearrangements activating the expression of TCL1 and MTCP1 (Pekarsky et al, 2001) and, furthermore, trisomy 8q associated with increased MYC expression occurs frequently in Tcell prolymphocytic leukaemia (Maljaie et al, 1995). Transgenic mice overexpressing TCL1 or MTCP1 in T cells usually developed late-onset CD4 À CD8 þ T-cell tumours, however, rather than the CD4 þ CD8 À neoplasms they aimed to model (Pekarsky et al, 2001).…”

Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32)

“…1,3,6 These rearrangements juxtapose enhancer elements of the TCRAD locus in 14q11 next to oncogenes located within the TCL1 locus in 14q32, whose expression is then deregulated. [7][8][9] Besides the inv (14), which is regarded as the primary oncogenic event in T-PLL, 7-10 the tumor cells usually harbor a high load of additional chromosomal aberrations. 3,6 These secondary chromosomal aberrations include overrepresentations of 8q and deletions of 8p, frequently due to formation of an isochromosome iso(8q), 3,6 as well as losses on chromosome 11, 11,12 and with lower frequency involving other chromosomal regions like 22q and 6q.…”