Synergistic effects of MALT1 inhibitor and selinexor on Acute Myeloid Leukemia cells and the underlying mechanisms

Abstract Background: Current treatment of acute myeloid leukemia (AML) is primarily based on combination chemotherapy, which has certain limitations. Therefore, the development of novel targeted therapeutics is urgently needed for the treatment of AML. MALT1 inhibitors have been shown to induce apoptosis in various hematological malignancies, whereas selinexor has demonstrated clinical efficacy in AML. This study investigated the synergistic anti-leukemic potential of the MALT1 inhibitor MI2 in combination with selinexor and elucidated the underlying molecular mechanisms. Methods: To investigate the effects of combined MALT1 inhibition and selinexor treatment on cell viability, apoptosis, and related signaling pathways in AML, we treated THP-1 and MOLM-13 AML cell lines with MI2 and/or selinexor. Cell viability was measured by CCK-8 assay; demonstrated the synergistic effect by calculating the combination Index; apoptosis was quantified via flow cytometry (Annexin V/PI); protein expression of apoptotic markers (cleaved caspase-3, PARP-1), anti-apoptotic regulators (Bcl-xL), and NF-κB components (p65, c-Rel) was analyzed by Western blotting. Results: The MALT1 inhibitor MI2 and the XPO1 inhibitor selinexor suppressed proliferation in THP-1 and MOLM-13 AML cell lines monotherapies , exhibiting concentration- and time-dependent effects . Combinatorial treatment of MI2 and selinexor synergistically inhibited AML cell proliferation , with efficacy progressively enhanced by increasing exposure duration and drug concentrations. Individually , both agents significantly induced apoptosis in AML cells; critically , their combination substantially amplified apoptotic activation . This combination therapy enhanced the pro-apoptotic effects of the individual agents on AML cells by upregulating caspase-3 and PARP-1, and downregulating the anti-apoptotic proteins Bcl-xL and NF-κB pathway-associated proteins (P65 and c-Rel). Conclusions: The MALT1 inhibitor MI2 in combination with selinexor synergistically promotes apoptosis in AML cell lines by downregulating the anti-apoptotic protein Bcl-xL and inhibiting the activation of the NF-κB pathway. This strategy represents a promising therapeutic approach for treating AML.