Mesenchymal Stromal Cell-Derived MMP14 Facilitates Leukemia Progression and Chemotherapy Resistance

Abstract

Abstract i ntroduction:Acute Myeloid Leukemia (AML) stands as a menacing hematological malignancy, characterized by the aberrant proliferation and development of myeloid cells, entailing formidable therapeutic complexities. Matrix metalloproteinases (MMP) represent pivotal enzymes that dismantle the extracellular matrix by disintegrating tissue barriers. Among these, MMP14 assumes significance as it governs the invasion and metastasis of cancer cells, exhibiting heightened expression in solid tumors, including prostate cancer, colon cancer, pancreatic cancer, breast cancer, and skin cancer, thereby endorsing the invasiveness and metastatic potential of angiogenic inflammatory cancer cells. Nonetheless, the effect of abnormal expression of MMP14 derived from mesenchymal stem cells (MSCs) in AML patients upon the bone marrow microenvironment and AML pathogenesis, along with its underlying mechanism, remains unexplored. Methods: AML-MSCs were extracted from bone marrow samples of AML patients through whole bone marrow adherent culture. Lentiviral vectors carrying cDNA of the MMP14 gene and empty lentiviral vectors were meticulously constructed and subsequently introduced into AML-MSCs. Brdu and CFU-F assayed the proliferative capacity of knockdown and control MSCs, and osteogenic induced differentiation was performed in vitro on both groups of MSCs.AML cell lines Kasumi-1 and Molm-13 were subjected to co-culture with AML-MSCs to evaluate the migratory and invasive capabilities of AML cell lines , while the proliferative activity of AML cell lines was assessed via BrdU. Following co-cultivation, AML cell lines were exposed to 1μM cytarabine for 48 hours, and cell viability was gauged using flow cytometry. Moreover, CD34+ cells were isolated from leukemia patients' bone marrow using magnetic beads and co-cultivated with the aforementioned MSC groups to explore the impact of MMP14 derived from MSCs on the resistance of leukemia stem cells to cytarabine. Results: Knockdown of MMP14 reduces MSC proliferation and colony-forming ability while also impeding MSC osteogenic differentiation. AML cell lines subjected to co-culture with the MSC knockdown group exhibited a remarkable reduction in both invasion and migration abilities. The BrdU assay demonstrated a significant decrease in the proliferation rate of AML cell lines within the MMP14 knockdown group. Moreover, following 48 hours of cytarabine administration, flow cytometric analysis revealed a lower proportion of viable cells in the knockdown group when compared to the control group. The same trend was observed in primary cells, as evidenced by a decreased percentage of proliferating CD34+ cells within the knockdown group, along with a reduced proportion of viable cells following cytarabine treatment. Conclusion: The MMP14 derived from MSCs fosters AML progression and confers chemoresistance. Our study provides valuable insights into the significance of MMP14 in AML drug resistance and underscores its potential as a promising preclinical target for AML treatment. DisclosuresNo relevant conflicts of interest to declare.