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• W4213348669 abstract "Non-genetic cellular plasticity has recently emerged as a basis for therapeutic resistance in cancer. Therefore, a better understanding of cellular plasticity and adaptive state changes in myeloma cells and the immune microenvironment is critical to develop effective therapeutic approaches that can overcome drug resistance. We performed fluorescence activated cell sorting and full-length single-cell RNA sequencing of myeloma cells and CD45+ immune cells from the bone marrow of 8 patients with relapsed/refractory multiple myeloma (RRMM) treated on a clinical trial with elotuzumab, pomalidomide, bortezomib and dexamethasone (Elo-PVD; NCT02718833) before and after treatment. We discovered that the transcriptional states of single myeloma cells are highly distinct between individual patients, despite the presence of the same established genomic classifiers, such as t(11;14). Furthermore, distinct transcriptional states co-exist within individual patients. Leveraging the single-cell RNA sequencing data to reconstruct differentiation trajectories of the myeloma cells, we found that transcriptional states diverge from normal plasma cells towards more immature cells, of the B lymphoid lineage or entirely different hematopoietic lineages. Since cell states are controlled by a small set of interconnected transcriptional regulators, we investigated expression of transcription factors and epigenetic modifiers and found widespread deregulation. Using SCENIC to define gene-regulatory relationships, we identified a shared core regulatory network between RRMM patients with transcription factors, such as MYC, MEF2C and TCF3. However, we further detected patient-specific regulons, which provide critical insight into mechanisms driving inter-patient heterogeneity. Interestingly, these altered transcriptional states were associated with up-regulation of potential immunotherapeutic targets, such as CD20, CD19, CD33. Subsequently, we defined the effect of immunomodulatory treatment with Elo-PVD on the immune microenvironment with single cell resolution. A high degree of variation in NK cell subsets in RRMM patients is reflected in patient-specific subclusters, with CD56bright NK cells ranging from 2%-69%. Importantly, NK cell differentiation trajectories revealed a shift with treatment, indicating there is substantial plasticity in NK cell subsets. Differential expression of more than 2000 genes (qval < 0.01), including CD16 and effector molecules PRF1, GNLY and GZMB, was indicative of widespread transcriptional reprogramming, which is therapeutically relevant. In conclusion, we find that higher transcriptional diversity and activation of alternate gene regulatory programs facilitate the emergence of altered transcriptional states in myeloma cells and the immune microenvironment. Interestingly, these altered states are associated with up-regulation of putative immune-therapeutic targets in myeloma cells, thus providing novel therapeutic vulnerabilities." @default.
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• W4213348669 date "2019-10-01" @default.
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• W4213348669 title "Defining the differentiation states of multiple myeloma at single cell resolution – Identifying opportunities for immunotherapy" @default.
• W4213348669 doi "https://doi.org/10.1016/j.clml.2019.09.102" @default.
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