TXNIP induces growth arrest and enhances ABT263-induced apoptosis in mixed-lineage leukemia-rearranged acute myeloid leukemia cells.,FEBS Open Bio

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TXNIP induces growth arrest and enhances ABT263-induced apoptosis in mixed-lineage leukemia-rearranged acute myeloid leukemia cells.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-06-24 , DOI: 10.1002/2211-5463.12908
Mina Noura _{1,

2} , Hidemasa Matsuo ₁ , Asami Koyama ₁ , Souichi Adachi _{1,

3} , Hiroshi Masutani ₂

Affiliation

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.

中文翻译：

TXNIP 在混合谱系白血病重排的急性髓系白血病细胞中诱导生长停滞并增强 ABT263 诱导的细胞凋亡。

硫氧还蛋白相互作用蛋白（TXNIP）已被广泛认为是多种癌症的肿瘤抑制因子，包括肝癌、乳腺癌和甲状腺癌。尽管与许多癌细胞一样，TXNIP 在急性髓性白血病 (AML) 细胞中表观遗传沉默，但其在白血病发生中的作用仍然难以捉摸。AML 中的混合谱系白血病 (MLL) 基因重排与预后不良有关，人们热切期待开发一种新的治疗方法。在这项研究中，我们首先揭示了 TXNIP 的低表达与 AML 患者的总生存期缩短有关。此外，我们证明 TXNIP 过表达显着抑制了携带 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 LC3B 的脂化来促进自噬。我们还表明，TXNIP 过表达与 ABT263（一种 Bcl-2 和 Bcl-xL 的强效抑制剂）相结合，在诱导 MLL 重排（MLL-r）AML 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 有前景的治疗靶点的潜力。

更新日期：2020-06-24

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