Abstract
Overcoming drug-resistance and the subsequent relapse that often occurs with monotherapy is crucial in the treatment of acute myeloid leukemia. We here demonstrate that therapy-resistant leukemia initiating cells can be targeted using a novel inhibitor of mitochondrial transcription (IMT). The compound inhibits mitochondrial RNA polymerase activity and sensitizes the resistant population to the induction of apoptosis. In vitro studies on acute myeloid leukemia cells demonstrate that IMT prevents cell proliferation, and together with a selective BCL-2 inhibitor, venetoclax, induces apoptosis and suppress oxidative phosphorylation (OXPHOS) synergistically. AML mouse models treated with IMT in combination with venetoclax show prolonged survival in venetoclax-resistant models. Our findings suggest that certain therapy-resistant leukemia cell populations display a unique dependency on mitochondrial transcription and can be targeted with IMT.
Competing Interest Statement
CMG is a scientific co-founder of Pretzel Therapeutics Inc. Together with RD, TB, AU, PN, BMK who are employees of LDC, CMG is also co-inventor of the patent application WO 2019/057821. Medicinal chemistry and pharmacology part of this work was financed by the Max-Planck Gesellschaft e.V. under the framework agreement between Max-Planck and LDC.
Footnotes
This version of the manuscript has been revised based on reviewer feedback from our previous submission to eLife. Key updates include: Pathway Analysis: We have incorporated gene ontology (GO) analysis of transcriptomic data, highlighting pathways involved in mitochondrial function, immune signaling, and intracellular signaling, providing mechanistic insight into the drug combination. Synergy Analysis: A Bliss synergy matrix has been added to support the synergistic interaction between IMT and venetoclax, demonstrating enhanced inhibition of AML cell viability. Statistical Comparisons: We have included statistical analyses comparing venetoclax alone versus combination treatment (Fig. 5C) and clarified statistical methods for OXPHOS measurements. PDX Model Characterization: Additional details on the classification and genetic background of patient-derived xenograft (PDX) models have been included for better context. Bone Marrow Sanctuary Hypothesis: We now discuss the potential for leukemic cell persistence in the bone marrow, despite the absence of leukemia in peripheral blood, providing a rationale for disease relapse. Limitations & Future Directions: While our study focuses on mitochondrial inhibition, we acknowledge the importance of glycolysis measurements, liver and kidney toxicity assessments, and alternative AML therapy combinations, which we suggest for future research. These revisions enhance the manuscript's clarity and provide a more comprehensive interpretation of our findings.
