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Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance

Bruno Paiva, Luis A. Corchete, Maria-Belen Vidriales, Noemi Puig, Patricia Maiso, Idoia Rodriguez, Diego Alignani, Leire Burgos, Maria-Luz Sanchez, Paloma Barcena, Maria-Asuncion Echeveste, Miguel T. Hernandez, Ramón García-Sanz, Enrique M. Ocio, Albert Oriol, Mercedes Gironella, Luis Palomera, Felipe De Arriba, Yolanda Gonzalez, Sarah K. Johnson, Joshua Epstein, Bart Barlogie, Juan José Lahuerta, Joan Blade, Alberto Orfao, María-Victoria Mateos, Jesús F. San Miguel, Ernesto Pérez Persona, Antonia Sampol Mayol, Joan Bargay Lleonart, Eugenia Abella Monreal, Joan Bladé Creixentí, Miguel Granell Gorrochategui, Albert Oriol Rocafiguera, Albert Altes Hernández, Elena Rámila Herrero, Mercedes Gironella Mesa, Anna Sureda Balari, Carmen Cabrera Silva, Francisco Javier Capote Huelva, José Luis Guzmán Zamudio, María Mas Esteve, Carmen Calle Primo, José Luis Bello López, Carlos Cerveró Santiago, Yolanda González Montes, Dunia de Miguel Llorente, María Asunción Echeveste Gutiérrez, Fernando Escalante Barrigón, Raquel de Paz Arias, María Jesús Blanchard Rodríguez, Juan José Lahuerta Palacios, Isabel Krsnik Castello, Rafael Martínez Martínez, Adrián Alegre Amor, Cristina Encinas Rodríguez, Juan José Gil Fernández, Carolina Bombín Canal, Pilar Bravo Barahona, Francisco Javier Peñalver Párraga, Rebeca Iglesias del Barrio, Jaime Pérez de Oteyza, Eugenio Giménez Mesa, José Ángel Hernández Rivas, Ana Paz Lafuente Guijosa, María Casanova Espinosa, José María Moraleda Jiménez, Felipe de Arriba de la Fuente, María Ángeles Goñi Herranz, Felipe Prósper Cardoso, Jesús F. San Miguel Izquierdo, Alexia Suárez Cabrera, Marivi Mateos Mateos, Miguel Teodoro Hernández García, Eulogio Conde García, José Mariano Hernández Martín, Eduardo Ríos Herranz, Jesús Martín Sánchez, José Luis Bueno Cabrera, Felipe Casado Montero, Javier de la Rubia Comos, Paz Ribas García, Aurelio López Martínez, Ana Isabel Teruel Casasus, María Ángeles Ruíz Guinaldo, Elena Amutio Díez, Monserrat Pérez Sánchez, Luis Palomera Bernal and Pilar Delgado Beltrán on behalf of Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas (GEM/PETHEMA) Cooperative Study Groups

Key Points

  • We report for the first time the biological features of MRD cells in MM and unravel that clonal selection is already present at the MRD stage.

  • MRD cells show a singular phenotypic signature that may result from persisting clones with different genetic and gene expression profiles.

Abstract

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 overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were 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. This trial was registered at www.clinicaltrials.gov as #NCT01237249.

  • Submitted August 20, 2015.
  • Accepted December 28, 2015.
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