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Article Abstract
MLL gene rearrangement recurrently occurs in acute myeloid leukemia (MLL-r AML), which is closely associated with chemotherapy insensitivity and unfavorable clinical outcomes. More importantly, there are limited therapeutic options for the management of patients with MLL-r AML, thus necessitating novel effective treatment strategies. In this study, we demonstrated that low doses of triptolide (LD TPL) and the XPO1 inhibitor selinexor exerted synergistic therapeutic effects on poor-outcome MLL-r AML in vitro, ex vivo and in vivo. Induction of mitochondrial outer membrane permeabilization (MOMP) and initiation of the mitochondrial apoptotic pathway were closely involved in the therapeutic synergy of LD TPL in combination with selinexor against MLL-r AML. Mechanistically, MYC downregulation mediated by the Rap1/Raf/MEK/ERK pathway rather than by PI3K/AKT signaling was implicated in the synergistic activity of the combined regimen. In addition, the induction of DNA damage also contributed to the synergistic effects of the combined regimen on MLL-r AML. In summary, our findings suggest that LD TPL in combination with selinexor might represent a promising therapeutic approach for the treatment of MLL-r AML. However, future clinical trials are mandatory to draw a decisive conclusion.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141074 | PMC |
| http://dx.doi.org/10.1016/j.tranon.2025.102399 | DOI Listing |
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Article Synopsis
- Acute myeloid leukemia (AML) is a serious blood cancer characterized by frequent relapses, partly due to disruptions in chromatin modifications that affect cell behavior.
- Aberrant histone modifications lead to the activation of self-renewal genes in specific hematopoietic progenitor cells, which are crucial for the development of AML, particularly in cases with MLL rearrangements and NPM1 mutations.
- New research highlights how leukemic cells exploit histone modification complexes as potential treatment targets, and the review suggests combining therapies that inhibit these complexes to improve effectiveness and tackle resistance to current treatments.