Sejima Hiroe, Naito Tadasuke, Fukushima Takuya, Saito Mineki
Department of Microbiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
Laboratory of Hematoimmnology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Okinawa, 903-0215, Japan.
Retrovirology. 2025 Mar 25;22(1):3. doi: 10.1186/s12977-025-00660-7.
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.
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.
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.
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.
肿瘤抑制因子Menin在遗传性和散发性内分泌肿瘤中均易发生突变，它与其直接靶点Bach2通过调节CD4+T细胞衰老和维持细胞因子稳态，在预防自身免疫中发挥关键作用。由于1型人类T细胞白血病病毒（HTLV-1）主要感染CD4+T细胞，其失调会导致成人T细胞白血病/淋巴瘤（ATL）的血液系统恶性肿瘤以及HTLV-1相关脊髓病/热带痉挛性截瘫（HAM/TSP），我们研究了Menin-Bach2通路在HTLV-1感染中的作用。
分析了HTLV-1感染和未感染的人T细胞系、ATL患者、HAM/TSP患者及无症状携带者外周血单个核细胞（PBMC）中menin和bach2的mRNA表达。此外，还评估了Menin或Bach2与Tax或HBZ之间的相互作用；这些蛋白的亚细胞定位；menin、tax和HBZ基因敲低的影响；以及menin与其辅因子混合谱系白血病（MLL）之间的相互作用抑制剂对HTLV-1感染的T细胞增殖的影响。
研究结果如下：（1）在所有测试的8种HTLV-1感染的T细胞系中，均表达了Menin蛋白，而其中5种细胞系中未检测到Bach2表达；（2）HAM/TSP患者和ATL患者的PBMC中menin和bach2的mRNA水平均显著降低；（3）Tax和HBZ均分别与Menin和Bach2发生物理相互作用；（4）在HTLV-1转化的T细胞系MT-2和SLB-1中，敲低tax而非HBZ可下调Bach2表达，但不影响Menin表达；（5）敲低menin可下调MT-2中Bach2的表达，但对SLB-1无影响；（6）Menin-MLL相互作用抑制剂可抑制MT-2的细胞生长，但对SLB-1无效；（7）HBZ和Menin在MT-2和SLB-1中的亚细胞定位不同。
HTLV-1感染改变了控制细胞增殖的Menin-Bach2通路的调节。当Menin失去对Bach2表达的控制时，Menin-MLL相互作用抑制剂在抑制细胞增殖方面失去效力。Menin-Bach2通路的失调可能有助于HTLV-1相关疾病的发病机制。
