Rearranged NF‐κB2 gene in an adult T‐cell leukemia cell line

Abstract

Adult T-cell leukemia (ATL) is an aggressive type of leukemia, originating from T-cells infected with human T-cell leukemia virus type 1. Accumulating evidence suggests the aberrant activation of NF-κ κ κ κB to be a causative factor mediating the abnormal proliferation of leukemic cells, thus resulting in the development of ATL. A rearranged NF-κ κ κ κB2/p100 gene was isolated from an ATL-derived cell line, which was generated by a chromosomal translocation. The isolated NF-κ κ κ κB2 mutant is fused with the with no (lysine) deficient protein kinase 1 gene, coding for a 58 kDa protein that retains the DNA binding Rel homology domain, but it lacks the entire ankyrin repeat inhibitory domain, thus suggesting its constitutive activation. This rearranged NF-κ κ κ κB2 gene product (p58) was localized in the nucleus, and formed a complex with NF-κ κ κ κB p65 or RelB. Moreover, a T-cell line expressing p58 increased the amount of an NF-κ κ κ κB2-inducible gene, NF-κ κ κ κB2/p100 by itself. These results suggest that such NF-κ κ κ κB2 gene rearrangement may therefore be a factor in the constitutive activation of NF-κ κ κ κB in ATL, and thereby playing a role in the ATL pathogenesis. A dult T-cell leukemia (ATL) is a highly aggressive leukemia, characterized by the clonal proliferation of CD4 positive T-cells infected with human T-cell leukemia virus type 1 (HTLV-1).(1-5) HTLV-1 establishes a life-long persistent infection through the immortalization of infected T-cells. (6,7) This immortalization is, however, not sufficient for ATL development, since only a minority of HTLV-1 infected individuals (approximately 5%) develop ATL after a long latency period (approximately 60 years).(4,5) Accumulating evidence indicates that genetic and epigenetic changes of the host genome and HTLV-1-associated deterioration of host immunity may therefore be major factors in ATL development. (4,5) Primary leukemic cells in the patients, as well as ATL-derived cell lines demonstrate the constitutive activation of transcription factor NF-κB.(8-11) Moreover, agents which block the NF-κB activity induce apoptosis in these ATL cells.(12-14) Although HTLV-1 Tax protein potently activates NF-κB, primary leukemic cells as well as ATL derived cell lines express little, if any, tax mRNA. This indicates that the NF-κB activation in ATL cells is caused by genetic and/or epigenetic changes in the host genome. (4,10,15,16) However, precisely how NF-κB is deregulated in ATL cells still remains poorly elucidated.NF-κB plays a crucial role in cell proliferation, apoptosis, as well as inflammation, differentiation and development, by regulating the transcription of numerous genes.(17,18) NF-κB is a family of factors containing the DNA binding Rel homology domain including p50, p65, c-Rel, RelB, and p52. NF-κB is normally sequestered in the cytoplasm through physical interaction with ankyrin-repeat-containing inhibitor proteins, including IκBα, IκBβ, IκBε, and NF-κB2/p100. NF-κB is activated by either the canonical or non-canonical pathway. In the canonical ...

NF‐κB and the link between inflammation and cancer

“…As described above, considerable biochemical and genetic evidence exists linking the NF‐κB pathway to the pathogenesis of a wide range of human cancers, including both solid and hematopoietic malignancies. A few chromosomal translocations can lead to NF‐κB activation in cancer, such as those affecting the NF‐κB2 locus (40, 155). Several well‐characterized oncogenes can induce NF‐κB activity, but in most solid malignancies, NF‐κB is activated in response to inflammatory signals generated within the tumor microenvironment.…”

Dynamic roles for NF‐κB in HTLV‐I and HIV‐1 retroviral pathogenesis

“…In addition, Tax potentiates the expression and induction of other Rel transcription factors, including p100/p52 and c‐Rel, both proto‐oncogene candidates, in a feedforward loop (64, 89). Chromosomal translocation of the p100/p52 gene resulting in the removal of the inhibitory carboxyl terminal ankryin repeat domain has been reported in various forms of human lymphoma and in at least one case of ATL (90, 91). Moreover, short interfering RNA (siRNA) knockdown of p100/p52 compromises the ability of Tax to convert a T‐cell line (CTLL‐2) from IL2‐dependent growth to IL‐2‐independent growth, suggesting p100/p52 contributes to cellular transformation in HTLV‐I infected cells (92).…”

“…Thus, a key function of ARD is to guard against aberrant constitutive processing of p100 into p52 (124, 133). Chromosomal truncation of the p100/p52 gene, resulting in the nuclear expression of p100ΔC and p52, is frequently observed in lymphoid malignancies (90, 91).…”

Human T-Cell Lymphotropic Virus: A Model of NF-κB-Associated Tumorigenesis

“…For example, DNA damage, a determining factor in tumorigenesis including ATL leukemogenesis [147,148], can lead to strong NF-κB activation [111]. On the other hand, epigenetic up-regulation of NIK expression and genetic deletions of the p100 C-terminus have recently been detected in certain ATL cells [149–151]. While NIK is a potent activator of both canonical and noncanonical NF-κB pathways [32,55,96], C-terminal deletions of p100 results in constitutive p100 processing and non-canonical NF-κB activation [32,152,153].…”