Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

Biochemistry Basic Medical Sciences Hematology Life Sciences Oncology Medicine Cell Biology
Acute Myeloid Leukemia Stem Cells Mitochondrial Calcium Oxidative Phosphorylation Drug Resistance

The Discovery Process of This Study

This is an academic paper report on the study of acute myeloid leukemia (AML) stem cells. The study found that venetoclax treatment targeting the BCL-2 protein induces different mitochondrial calcium signaling changes in drug-sensitive and drug-resistant AML stem cells, thereby affecting their oxidative phosphorylation metabolism and survival.

The study aims to explore the mechanism of venetoclax treatment in AML stem cells. Previous research found that venetoclax could target oxidative phosphorylation metabolism-sensitive AML stem cells, but the metabolism of resistant cells remained unaffected. BCL-2 protein is known to regulate intracellular calcium ion dynamics, leading the authors to hypothesize that calcium signaling might be related to venetoclax treatment responsiveness.

Research Process:

  1. Transcriptome analysis revealed a significant upregulation of calcium-mediated signaling pathways in drug-resistant AML cells.

  2. Single-cell transcriptome sequencing showed that calcium-mediated signaling pathways were upregulated across multiple cell subpopulations (progenitor, monocyte, promyelocyte) in drug-resistant patients.

  3. Measurements revealed that the baseline mitochondrial calcium levels in drug-resistant AML stem cells were significantly elevated compared to sensitive samples.

  4. In sensitive AML samples, short-term venetoclax treatment induced mitochondrial calcium overload and lowered SERCA protein levels, subsequently inhibiting oxidative phosphorylation. This effect could be replicated by SERCA inhibitors.

  5. In contrast, venetoclax did not induce the aforementioned calcium signaling changes in drug-resistant AML cells. Instead, they exhibited higher MCU protein expression and a dependency on mitochondrial calcium.

  6. Targeting MCU (mitochondrial calcium uniporter) inhibited the oxidative phosphorylation and colony-forming ability of drug-resistant AML stem cells.

  7. The already marketed chemotherapy drug mitoxantrone, at low doses, could inhibit MCU, thereby specifically clearing drug-resistant AML stem cells.

  8. In mouse xenograft models, mitoxantrone pretreatment inhibited the colony-forming ability of drug-resistant AML cells.

Summary:

This study discovered that venetoclax regulates calcium signaling differently in sensitive and resistant AML stem cells and revealed the critical role of mitochondrial calcium dynamics in regulating AML stem cell metabolism and survival. Strategies targeting MCU (like mitoxantrone) hold potential as treatments for venetoclax-resistant AML.

People and Institutions:

The research was conducted by Craig T. Jordan’s group at the University of Colorado Anschutz Medical Campus. Craig T. Jordan is the corresponding author, with significant contributions from Anagha Inguva Sheth, Mark J. Althoff, Hunter Tolison, and others.

Significance:

  1. Elucidated the role of calcium ion dynamics in regulating AML stem cell metabolism and survival.

  2. Discovered a unique dependency on mitochondrial calcium in drug-resistant AML stem cells, providing a new target for treating venetoclax resistance.

  3. Suggested that the already marketed drug mitoxantrone at low doses might serve as an adjunct therapy for alleviating venetoclax resistance in AML.

  4. Provided new ideas for individualized and precise treatment of AML.