Journal
LEUKEMIA
Volume 31, Issue 2, Pages 382-392Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.211
Keywords
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Categories
Funding
- Cooperative Research Thematic Network of the Red de Cancer (Cancer Network of Excellence) [RD12/0036/0048, RD12/0036/0058, RD12/0036/0046, RD12/0036/0068, RD12/0036/0069, RD12/0036/0061]
- Instituto de Salud Carlos III, Spain, Instituto de Salud Carlos III/Subdireccion General de Investigacion Sanitaria [FIS: PI060339, 06/1354, 02/0905, 01/0089/01-02, PS09/01897/01370, PI13/01469, PI14/01867, G03/136, Sara Borrell: CD13/00340, CD12/00540]
- Fundacio La Marato de TV3 [20132130-31-32]
- Asociacion Espanola Contra el Cancer [GCB120981SAN]
- International Myeloma Foundation (IMF) Junior Grant
- Black Swan Research Initiative of the IMF
- Multiple Myeloma Research Foundation
- Qatar National Research Fund (QNRF) Award [7-916-3-237]
- Marie Curie [LincMHeM-330598]
- AACR-Millennium Fellowship in Multiple Myeloma Research [15-40-38-PAIV]
- Leukemia Research Foundation
- European Research Council (ERC)
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The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 - CD81 expression axis identifies three bone marrow (BM) PC subsets with distinct age- prevalence, proliferation, replication- history, immunoglobulin- production, and phenotype, consistent with progressively increased differentiation from CD19+ CD81+ into CD19 - CD81+ and CD19 - CD81 - BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 - CD81 -) clones, 38% intermediate- differentiated (CD19 - CD81+) and 3% less- differentiated (CD19+ CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression- free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal- residual- disease samples (n = 40) unraveled that in 20% of patients, less- differentiated PCs subclones become enriched after therapy- induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less- differentiated clonal PCs retain high expression of genes related to preceding B- cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less- differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
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