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| Status |
Public on Jan 28, 2016 |
| Title |
Phenotypic and genomic analysis of multiple myeloma minimal residual disease clonal plasma cells: a new model to understand chemoresistance [CytoScan750K Copy Number, LOH] |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
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| Summary |
Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) relates to inferior survival in multiple myeloma (MM). MRD PCs are therefore a minor clone able to recapitulate the initial tumor burden at relapse and accordingly, its characterization may represent a unique model to understand chemoresistance; unfortunately, the MRD clone has never been biologically 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 clone is enriched by cells over-expressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4) and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs. diagnostic PCs showed identical copy number alterations (CNAs) in 3/8 cases, 2 patients with linear acquisition of additional CNAs in MRD clonal PCs, and 3 cases with variable acquisition and loss of CNAs over time. The MRD clone showed significant downregulation of genes particularly related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and identifies chemoresistant PCs in vitro. Together, we show that therapy-induced clonal selection is already present at the MRD stage, in which chemoresistant PCs show a specific phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles.
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| Overall design |
Per-protocol, clonal PCs from diagnostic samples were isolated from BM aspirates using CD138+ immunomagnetic beads (Miltenyi Biotech, Bisley, UK). Following induction therapy, BM aspirates were taken to determine patients’ MRD response at cycle 9, and clonal PCs from MRD-positive cases were FACS-sorted (FACSAria II, BDB; purity ≥97%) according to patient-specific aberrant phenotypes. DNA from matched diagnostic and MRD clonal PCs was available in 8 patients. Afterwards, genome-wide detection of copy-number abnormalities (CNAs) and loss of heterozygosity (LOH) were investigated using the standard Affymetrix Cytoscan 750K platform (Affymetrix, Santa Clara, CA, USA). An unpaired analysis was performed using 240 Hapmap files as reference for normal DNA. The complete data set was analyzed by visual inspection using the AGCC and ChAS software programs (Affymetrix). CNAs were reported when the three following criteria were met: ≥25 consecutive imbalanced markers per segment; ≥100Kb minimum genomic size and; <50% overlap with paired control DNA and/or genomic variants of Toronto DB (DGV). Only copy number-neutral LOH (CNN-LOH) larger that 5Mb were considered.
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| Contributor(s) |
Paiva B, Corchete LA, Gutierrez NC, Vidriales M, Maiso P, Rodriguez I, Alignani D, Sanchez ML, Barcena P, Echeveste M, Hernandez MT, García-Sanz R, Ocio EM, Oriol A, Gironella M, Palomera L, De Arriba F, Gonzalez Y, Lahuerta J, Blade J, Orfao A, Epstein J, Barlogie B, Mateos M, San Miguel JF |
| Citation(s) |
26755711 |
| Submission date |
Jun 30, 2015 |
| Last update date |
Jan 28, 2016 |
| Contact name |
Bruno Paiva |
| E-mail(s) |
bpaiva@unav.es
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| Organization name |
Clinica Universidad de Navarra
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| Street address |
Av. Pio XII, 55
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| City |
Pamplona |
| ZIP/Postal code |
31008 |
| Country |
Spain |
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| Platforms (1) |
| GPL18637 |
[CytoScan750K_Array] Affymetrix CytoScan 750K Array |
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| Samples (24)
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| This SubSeries is part of SuperSeries: |
| GSE70399 |
Phenotypic and genomic analysis of multiple myeloma minimal residual disease clonal plasma cells: a new model to understand chemoresistance |
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| Relations |
| BioProject |
PRJNA288530 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE70397_ChAS_Log2_Ratios.txt.gz |
59.4 Mb |
(ftp)(http) |
TXT |
| GSE70397_RAW.tar |
1.5 Gb |
(http)(custom) |
TAR (of CEL, CYCHP, TXT) |
| GSE70397_Samples_P9-P12_ChAS_Log2_Ratios.txt.gz |
31.7 Mb |
(ftp)(http) |
TXT |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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