TXNIP induces growth arrest and enhances ABT263-induced apoptosis in mixed-lineage leukemia-rearranged acute myeloid leukemia cells.
TXNIP induces growth arrest and enhances ABT263-induced apoptosis in mixed-lineage leukemia-rearranged acute myeloid leukemia cells.
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TXNIP 在混合谱系白血病重排的急性髓性白血病细胞中诱导生长停滞并增强 ABT263 诱导的细胞凋亡。
DOI：
10.1002/2211-5463.12908
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Hiroshi Masutani.
中科院分区：
文献类型：
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作者：
Mina Noura;Hidemasa Matsuo;Asami Koyama;Souichi Adachi;Hiroshi Masutani.
硫氧还蛋白相互作用蛋白（TXNIP）已被广泛认为是各种癌症的肿瘤抑制因子，包括肝癌，乳腺癌和甲状腺癌。尽管TXNIP在急性髓性白血病（AML）细胞中表观遗传学沉默，如在许多癌细胞中一样，但其在白血病发生中的作用仍然难以捉摸。AML中的混合系白血病（MLL）基因重排与预后不良相关，迫切期待开发新的治疗方法。在这项研究中，我们首次发现TXNIP的低表达与AML患者总生存期缩短相关。此外，我们证明TXNIP过表达显著抑制携带MLL融合基因的AML细胞的增殖。TXNIP通过增加自噬蛋白Beclin 1的表达和LC 3B的脂化来促进自噬。我们还表明，TXNIP过表达与Bcl-2和Bcl-xL的有效抑制剂ABT 263组合，在诱导MLL-重排（MLL-r）AML细胞中的细胞死亡方面非常有效。总之，这项研究提供了对TXNIP介导的肿瘤抑制的分子机制的见解，并进一步强调了TXNIP作为MLL-r AML有前途的治疗靶点的潜力。
Thioredoxin‐interacting protein (TXNIP) has been widely recognized as a tumor suppressor in various cancers, including liver, breast, and thyroid cancers. Although TXNIP is epigenetically silenced in acute myeloid leukemia (AML) cells, as in many cancer cells, its role in leukemogenesis remains elusive. Mixed‐lineage leukemia (MLL) gene rearrangements in AML are associated with poor prognosis, and the development of a new treatment method is eagerly anticipated. In this study, we first reveal that lower expression of TXNIP is correlated with shortened overall survival periods in AML patients. Moreover, we demonstrated that TXNIP overexpression significantly suppresses proliferation in AML cells harboring MLL fusion genes. TXNIP promotes autophagy by increasing expression of the autophagy protein, Beclin 1, and lipidation of LC3B. We also show that TXNIP overexpression combined with ABT263, a potent inhibitor of Bcl‐2 and Bcl‐xL, is highly effective at inducing cell death in MLL‐rearranged (MLL‐r) AML cells. In summary, this study provides insights into the molecular mechanism of TXNIP‐mediated tumor suppression and furthermore underscores the potential of TXNIP as a promising therapeutic target for MLL‐r AML.