Abstract
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.
Highlights
Thioredoxin-interacting protein (TXNIP) is epigenetically silenced in acute myeloid leukemia (AML) cells, as in many cancer cells, its role in leukemogenesis remains elusive
We first analyzed the clinical datasets, and we revealed that lower TXNIP expression was associated with poor prognosis in patients with refractory AML and relapsed AML (Fig. 1A)
TXNIP expression is different among AML subgroups, we further analyzed clinical datasets and found that TXNIP expression was most decreased in Mixed-lineage leukemia (MLL)-r
Summary
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. We demonstrated that TXNIP overexpression significantly suppresses proliferation in AML cells harboring MLL fusion genes. 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. This study provides insights into the molecular mechanism of TXNIP-mediated tumor suppression and underscores the potential of TXNIP as a promising therapeutic target for MLL-r AML. Rearrangements of MLL gene are found in 5–10% of all acute leukemia and in up to 85% of secondary leukemia after treatment with. It is eagerly desired to identify the underlying factors of malignancy and to develop a new therapeutic strategy for refractory
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