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- Title
OAB-014: Newly diagnosed Multiple Myeloma patients with high levels of circulating tumor cells are distinguished by increased bone marrow plasma cell proliferation.
- Authors
Fokkema, A. Cathelijne; Jong, Madelon de; Tahri, Sabrin; Kellermayer, Zoltán; den Hollander, Chelsea; Vermeulen, Michael; Papazian, Natalie; van Duin, Mark; Broijl, Annemiek; Sonneveld, Pieter; Cupedo, Tom
- Abstract
Circulating tumor cells (CTCs) are present in the blood of all patients with (precursor)stages of Multiple Myeloma (MM). The levels of CTCs vary widely between patients, yet the biology behind this variability is unknown. Importantly, MM patients with a higher percentage of CTCs have an inferior prognosis independent of high-risk cytogenetics, suggesting that CTC numbers are a relevant reflection of tumor cell biology. Here, we set out to identify differences in CTCs and paired bone marrow plasma cells (BM PCs). Additionally, we compared BM PCs from patients with high and low levels of CTCs with the goal of identifying mechanistic drivers of high-risk disease. We isolated PCs from viably frozen mononuclear cells of peripheral blood and bone marrow aspirates of newly diagnosed MM patients. Common high-risk mutations were present in both groups. We performed single cell RNA sequencing of paired CTCs and BM PCs from five patients with a high percentage of CTCs (0.5%-8%). In addition, we generated single cell transcriptomes of BM PCs of eight patients with a high percentage of CTCs (2-22%) and 13 patients with low percentage of CTCs (0.004%-0.08%) Single cell transcriptomes were generated from 44,779 CTCs and 35,697 bone marrow PCs. When paired CTCs and BM PCs were integrated, we identified 9 common clusters, no cell specific cluster for either source was detected. Moreover, only 25 genes were significantly differentially expressed between CTCs and BM PCs. The absence of unique clusters in either CTCs or BM PCs, and the transcriptional overlap between these two sources indicate that CTC levels are not driven by the emergence of a transcriptionally different migratory clone, but are likely a reflection of altered BM PC biology. To identify such alterations, we compared bone marrow PCs from patients with high and low percentages of CTCs. Single cell transcriptomes were generated from 74,830 bone marrow PCs. Integration of all patients lead to the identification of 8 distinct PC clusters, one of which was characterized by active proliferation as defined by transcription of STMN1 and MKI67. Interestingly, this proliferative cluster was larger in patients with a high percentage of CTCs. Furthermore, cell cycle analyses based on canonical G2M and S phase markers revealed that actively cycling PCs were more frequent in the BM of patients with a high percentage of CTCs (64% versus 30%, p<0.001), irrespective of the cluster in which these cells were contained. Through single cell transcriptomic analyses we reveal that CTCs and MM cells from BM are transcriptionally similar. Importantly, we identify increased BM PC proliferation as a significant difference between patients with high and low levels of CTCs, implicating an increased entry into the cell cycle as one of the mechanisms driving CTC levels and MM disease pathobiology.
- Publication
Clinical Lymphoma, Myeloma & Leukemia, 2021, Vol 21, pS9
- ISSN
2152-2650
- Publication type
Article
- DOI
10.1016/S2152-2650(21)02088-7