Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance
Paiva B (1), Corchete LA (2), Vidriales MB (2), Puig N (2), Maiso P (1), Rodriguez I (1), Alignani D (1), Burgos L (1), Sanchez ML (3), Barcena P (3), Echeveste MA (4), Hernandez MT (5), García-Sanz R (2), Ocio EM (2), Oriol A (6), Gironella M (7), Palomera L (8), De Arriba F (9), Gonzalez Y (10), Johnson SK (11), Epstein J (11), Barlogie B (11), Lahuerta JJ (12), Blade J (13), Orfao A (3), Mateos MV (2), San Miguel JF (14).
(1) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain;
(2) Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigacion del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain;
(3) Servicio General de Citometria, Centro de Investigacion del Cancer (IBMCC-USAL, CSIC), IBSAL, and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
(4) Hospital de Donostia, San Sebastian, Spain;
(5) Hospital Universitario de Canarias, Tenerife, Spain;
(6) Hospital Universitari Germans Trias i Pujol, Badalona, Spain;
(7) Hospital Vall de Hebron, Barcelona, Spain;
(8) Hospital Lozano Blesa, Zaragoza, Spain;
(9) Hospital Morales Meseguer, Murcia, Spain;
(10) Hospital Universitario Josep Trueta, Girona, Spain;
(11) Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, United States;
(12) Hospital 12 de Octubre, Madrid, Spain;
(13) Hospital Clinic, IDIBAPS, Barcelona, Spain.
(14) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM).
Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated.
Here, we compared the antigenic profile of MRD vs. diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study, and showed that the MRD subclone is enriched in cells over-expressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4) and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs. diagnostic PCs was performed in twelve patients; three of them showed identical copy number alterations (CNAs), in other three cases MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining six patients there were both CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage.
The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro.
Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles.
CITATION Blood. 2016 Jan 11. pii: blood-2015-08-665679.