Stem-Like Tumor Cells Confer Drug Resistant Properties to Mantle Cell Lymphoma

We have recently identified clonogenic malignant stem cell populations in human mantle cell lymphoma (MCL), is a particularly deadly subtype of Non-Hodgkin's Lymphoma (NHL). We have discovered that CD45+CD19-MCL cells, which we termed MCL-initiating cells (MCL-ICs), are highly tumorigenic and display self-renewal capacities in vivo; in contrast, CD45+CD19+ MCL cells, which constitute the vast majority of cells within the tumors, show no self-renewal capacities and display greatly reduced tumorigenicity. Given the newly appreciated roles of cancer stem cells in the drug resistance of some cancers, it is critical to investigate whether MCL-ICs play roles in drug resistance of human MCL.

CD45+CD19- and CD45+CD19+ cells isolated from MCL patients was tested for functional roles of MCL-ICs in drug-resistance of MCL using clinically-relevant chemotherapeutic regimens: R-CHOP, R-hyperCVAD, R-DHAP, R-HAD+B, and fludarabine-based regimen. We compared the cytotoxic effects and IC₅₀ values of above regimens between two cell groups. To understand molecular mechanisms of drug resistance of MCL-ICs, we examined the cell cycle status of MCL-ICs using Rhodamine 123.

Cytotoxicity assay showed that MCL-ICs are more resistant to clinically relevant combined chemotherapeutic regimens in vitro as compared to bulk MCL tumor cells. Annexin V apoptosis assay supported this finding. IC₅₀ values of chemotherapeutic agents that can induce the effective cytotoxicity of CD45+CD19-MCL-ICs were significantly higher than those of CD45+CD19+ MCL cells in most regimens. In contrast with CD45+CD19+ MCL cells, no significant growth inhibition was noted in CD45+CD19-MCL-ICs with combined drug treatments as well as a single agent. Rhodamine 123 efflux activity tests showed that MCL-ICs are maintained in a quiescent status.

We have discovered MCL-ICs were more resistant to various clinically relevant chemotherapeutic agents in combination or in a single regimen compared to CD45+CD19+ MCL cells. The resistance of MCL-ICs to drugs was largely due to quiescent properties with enriched ABC drug transporters. In conclusion, designing novel therapies that can kill MCL-ICs may prevent relapse and increase patient survival.

No relevant conflicts of interest to declare.