Single-Cell Multi-Omics Analysis Reveals Autologous Stem Cell Chemo-Mobilization with Etoposide +Cytarabine Plus G-CSF in Multiple Myeloma

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Introductions: We previously reported that autologous stem cell chem-mobilization with Etoposide +Cytarabine (EA) plus G-CSF was highly effective and safe for patients with multiple myeloma (MM). However, the state of mobilized CD34+ peripheral blood stem cells (PBSCs) and molecular mechanisms underlying its high-efficiency mobilization remain unknown. Methods: Here, we employed matched single-cell transcriptome and chromatin accessibility sequencing to profile CD34+PBSCs of patients with MM(n=12) mobilized with EA+ G-CSF (n = 9), plerixafor + G-CSF (n = 3), along with healthy allo-donors (n = 5) mobilized with G-CSF. In addition, we integrated single-cell transcriptomic data with public CXCR4 inhibitors or G-CSF mobilized PBSC transcriptomic data to obtain a comprehensive map of seven mobilization strategies. Results: The integrated map showed the alterations in the transcriptional landscape of mobilized PBSCs among mobilization strategies, revealing that EA plus G-CSF mobilized a higher fraction of hematopoietic stem cells (HSCs) and promoted a bias towards lymphoid differentiation compared to CXCR4 inhibitor and G-CSF. Meanwhile, CD34+ hematopoietic stem progenitor cells (HSPCs) mobilized by EA+G-CSF exhibited a higher proliferation capacity. We also explored the cellular and molecular basis of the high mobilization efficiency of CD34+ HSPCs by EA plus G-CSF in MM. Interestingly, we found that EA plus G-CSF mobilized CD34+ HSPCs exhibited significantly higher potential for cytarabine resistance, along with increased activity in the G-CSF signaling pathway and inflammatory response. The positive correlation between these three pathways suggested that chemotherapeutic agents may induce the endogenous G-CSF signaling pathway. Additionally, the JAK-STAT signaling pathway, which acts as a cross-talk mechanism between the G-CSF signaling pathway and the inflammatory response, also showed enhanced activity. Finally, we proposed the hypothesis of EA+G-CSF mobilization, suggesting that chemotherapeutic drug-induced changes in gene expression can either enhance (via the G-CSF pathway, RAC2, and ITGA4) or complement (via EGR1) the G-CSF mobilization process. Conclusion: EA plus G-CSF mobilized a significantly higher fraction of CD34+ HSPCs favoring the lymphoid as well as proliferative capacity. EA-induced transcriptional changes might promote or complement G-CSF mobilization process to enhance PBSC mobilization efficacy in MM.

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