Reference - Detail
| RRC ID | 85981 |
|---|---|
| Author | Sejima H, Naito T, Fukushima T, Saito M. |
| Title | Dysregulation of the tumor suppressor Menin and its target Bach2 in HTLV-1 infection. |
| Journal | Retrovirology |
| Abstract |
BACKGROUND:The tumor suppressor Menin, prone to mutations in both hereditary and sporadic endocrine tumors, along with its direct target Bach2, plays a crucial role in preventing autoimmunity by regulating CD4 + T cell senescence and maintaining cytokine homeostasis. Since human T-cell leukemia virus type 1 (HTLV-1) primarily infects CD4 + T cells, and its dysregulation contributes to both the hematological malignancy of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we examined the involvement of the Menin-Bach2 pathway in HTLV-1 infection. METHODS:The mRNA expression of menin and bach2 in HTLV-1-infected and uninfected human T-cell lines, peripheral blood mononuclear cells (PBMCs) from patients with ATL, HAM/TSP, and asymptomatic carriers were analyzed. Additionally, interactions between Menin or Bach2 and the Tax or HBZ; the subcellular localization of these proteins; the effect of knockdown of menin, tax, and HBZ genes; and the effects of interaction inhibitors between menin and its cofactor, mixed lineage leukemia (MLL), on the proliferation of HTLV-1-infected T cells were evaluated. RESULTS:The findings were as follows: (1) In all eight HTLV-1-infected T-cell lines tested, Menin protein was expressed, whereas Bach2 expression was absent in five of them; (2) the mRNA levels of both menin and bach2 significantly decreased in PBMCs from patients with HAM/TSP and ATL; (3) Tax and HBZ each physically interacted with both Menin and Bach2; (4) knockdown of tax, but not HBZ, downregulated Bach2, but not Menin expression in HTLV-1-transformed T-cell lines MT-2 and SLB-1; (5) knockdown of menin downregulated Bach2 expression in MT-2 but not in SLB-1; (6) A Menin-MLL interaction inhibitor suppressed cell growth of MT-2 but not in SLB-1; (7) HBZ and Menin exhibited different subcellular localization between MT-2 and SLB-1. CONCLUSIONS:HTLV-1 infection alters the regulation of the Menin-Bach2 pathway, which controls cell proliferation. The Menin-MLL interaction inhibitor loses its effectiveness in suppressing cell proliferation when Menin loses control over Bach2 expression. Dysregulation of the Menin-Bach2 pathway may contribute to HTLV-1-associated disease pathogenesis. |
| Volume | 22(1) |
| Pages | 3 |
| Published | 2025-3-25 |
| DOI | 10.1186/s12977-025-00660-7 |
| PII | 10.1186/s12977-025-00660-7 |
| PMID | 40128849 |
| PMC | PMC11934541 |
| MeSH | Adult Basic-Leucine Zipper Transcription Factors* / genetics Basic-Leucine Zipper Transcription Factors* / metabolism Cell Line Gene Products, tax / genetics Gene Products, tax / metabolism HTLV-I Infections* / genetics HTLV-I Infections* / metabolism HTLV-I Infections* / virology Human T-lymphotropic virus 1* / physiology Humans Leukemia-Lymphoma, Adult T-Cell / virology Leukocytes, Mononuclear / virology Proto-Oncogene Proteins* / genetics Proto-Oncogene Proteins* / metabolism Retroviridae Proteins |
| IF | 4.183 |
| Resource | |
| Human and Animal Cells | MOLT-4(RCB0206) Jurkat |