Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

Sheth, A. I.; Engel, K.; Tolison, H.; Althoff, M. J.; Amaya, M. L.; Krug, A.; Young, T.; Pei, S.; Patel, S. B.; Minhajuddin, M.; Winters, A.; Miller, R.; Shelton, I.; St-Germain, J.; Ling, T.; Jones, C.; Raught, B.; Gillen, A. E.; Ransom, M. R.; Staggs, S.; Smith, C.; Pollyea, D. A.; Stevens, B. M.; Jordan, C. T.

doi:10.1101/2023.10.02.560330

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bioRxiv · 10.1101/2023.10.02.560330

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

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Abstract

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance. SignificanceWe identify increased utilization of mitochondrial calcium as distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.

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Sheth, A. I., Engel, K., Tolison, H., Althoff, M. J., Amaya, M. L., Krug, A., Young, T., Pei, S., Patel, S. B., Minhajuddin, M., Winters, A., Miller, R., Shelton, I., St-Germain, J., Ling, T., Jones, C., Raught, B., Gillen, A. E., Ransom, M. R., Staggs, S., Smith, C., Pollyea, D. A., Stevens, B. M., Jordan, C. T.. 2023-10-03. Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium. https://doi.org/10.1101/2023.10.02.560330

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