MSC affect the sensitivity of CML cells to TKIs through mitochondrial transfered via tunneling nanotubes

Abstract Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myeloid leukemia (CML), but drug resistance remains a significant challenge. Our study aims to explore the impact of bone marrow microenvironment (BMM) mesenchymal stem cells (MSCs) on TKI therapy. Using a CML mouse model and cell lines, we found that CML cells extensively form tunneling nanotubes (TNTs) with MSCs, with unidirectional mitochondrial transfer from CML cells to MSCs via TNTs. Additionally, CML cells co-cultured with MSCs exhibited increased drug resistance. Following TKI treatment, CML cell metabolism was suppressed, and reactive oxygen species (ROS) levels were significantly reduced; however, with continued treatment, metabolism and ROS levels gradually recovered. In co-culture experiments with MSCs and CML cells, we similarly observed a significant reduction in CML cell ROS levels, accompanied by increased TKI resistance, regardless of prior TKI exposure, indicating that MSCs support CML cells by influencing their metabolism. Compared to normal cells, CML cells have higher ROS levels, and treatment with the ROS inhibitor N-acetylcysteine (NAC) increased CML cell resistance. However, in the MSC-CML co-culture system, NAC treatment significantly enhanced CML cell sensitivity to TKI drugs. We also observed the gradual formation of TNTs between CML cells and MSCs, facilitating mutual mitochondrial transfer. Therefore, we propose that during CML treatment, MSCs modulate CML cell metabolism and restore TKI sensitivity by transferring mitochondria via TNTs. Our study reveals the critical role of BMM cells in supporting CML cells through TNTs, suggesting that targeting this interaction could improve therapeutic outcomes for CML.