Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

Abstract

The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have IntroductionThe T-cell leukemia/lymphoma 1 (TCL1) gene maps to chromosome 14q31.2 and is involved in chromosomal translocations and inversions in T-cell prolymphocytic leukemia (T-PLL). It is also dysregulated in several B-cell malignancies, including B-cell chronic lymphocytic leukemia (B-CLL) and in germ cell tumors, such as seminoma and dysgerminoma. 1,2 Normally, Tcl1 protein is expressed in early embryos and fetal tissues, germ cells, and early T and B cells. [3][4][5] We previously showed that aggressive human CLLs overexpress Tcl1 6 and that transgenic mice expressing TCL1 in B cells developed an aggressive form of CLL. 7,8 These previous studies demonstrated that Tcl1 up-regulation is critical in the pathogenesis of the aggressive form of human CLL. Tcl1 is also known to be a coactivator of the Akt oncoprotein 9 and of the NF-B transcription pathway. 10 Despite efforts to clarify the molecular mechanisms of Tcl1 oncogenic function, the identification of specific pathways through which Tcl1 modulates oncogenic functions has been elusive. This was mainly because Tcl1 interacting proteins could not be identified by conventional methods aimed to isolate protein-protein complexes, with the exception of Akt, a protein unlikely to play a significant role in B-cell malignancies. 10,11 The ATM (ataxia-telangiectasia mutated) gene, located at chromosome 11q22.3, 12 is responsible for a rare disorder called ataxia-telangiectasia (AT), an autosomal recessive disease characterized by progressive cerebellar degeneration, variable immunodeficiency, genomic instability, and susceptibility to cancer, especially lymphoid malignancies. [12][13][14] ATM is thought to be a tumor suppressor gene because DNA double-strand breaks caused by ionizing radiation or chemicals result in rapid Atm autophosphorylation and activation, leading to checkpoint activation and phosphorylation of substrates that regulate cell-cycle progression, DNA repair, recombination, transcription, and cell death. 12,15 Atm is a Ser/Thr kinase responsible for the phosphorylation of many substrates, including p53, Nbs1, Chk2, H2A.X, Mdm2, 4E-BP1, and IB␣. IB␣ is an inhibitor of NF-B, a transcription factor involved in a variety of hematologic and solid tumor malignancies. 16 IB␣ 17-21 phosphorylation leads to its degradation followed by activation of NF-B. Atm has a carboxy-terminal sequence with significant homology to the catalytic domain of phosphatidylinositol-3-OH kinase (PI3K). 15 AKT is a downstream target of PI3K and interacts directly with Tcl1. 22 ATM biallelic loss in AT leads to chromosomal translocations and inversions at 14q31.2, resulting in Tcl1 overexpression in AT patients. Preleukemic and ...

TCL1A and ATM are co-expressed in chronic lymphocytic leukemia cells without deletion of 11q

“…This suggests that both genes are involved in similar cellular pathways. In line with previous reports that TCL1A knockdown reduces NF-κB activation, 9 knockdown of TCL1A in primary CLL cells induced apoptosis. The joint deregulation of TCL1A and ATM might therefore contribute to the massive accumulation of malignant cells in CLL patients.…”

“…Statistics were performed using unpaired t-test (***P<0.001; **P=0.001-0.01; *P=0.01-0.05). In line with a functional connection of TCL1A and ATM, a direct interaction of their gene products has recently been shown in CLL and linked to activated NF-κB signaling, 9 a pathway centrally involved in CLL pathogenesis 21 and apoptosis. 22 We therefore tested whether knockdown of TCL1A causes apoptosis of primary CLL cells (n=5).…”

“…Recently, a direct interaction of TCL1 and ATM proteins was reported in CLL in association with activation of the NF-kB pathway. 9 To assess the role of both genes in the resistance to apoptosis, we characterized their expression kinetics in CLL cells stimulated with different microenvironmental support.…”

A Sleeping Beauty screen reveals NF-kB activation in CLL mouse model

“…We and others previously showed the importance of NF-kB in CLL. [20][21][22][23] Because TCL1 is dysregulated in most of aggressive CLLs, it seems likely that the same genes are dysregulated in human CLLs overexpressing Tcl1.…”

TCL1 expression patterns in Waldenström macroglobulinemia

“…10 TCL1 has been shown to be overexpressed in chronic lymphocytic leukemia, 11,12 and its oncogenic role has been well established in transgenic mice. 13 It acts as an activator of Akt 14 and NF-kB 15 signaling in the cytoplasm, but may also function as a transcriptional regulator in the nucleus. 16 Increased TCL1 expression has been observed in other B-cell disorders 17,18 but not in multiple myeloma.…”