Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Bruno Paiva

PROVIDER: E-GEOD-70399 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Paiva Bruno B Corchete Luis A LA Vidriales Maria-Belen MB Puig Noemi N Maiso Patricia P Rodriguez Idoia I Alignani Diego D Burgos Leire L Sanchez Maria-Luz ML Barcena Paloma P Echeveste Maria-Asuncion MA Hernandez Miguel T MT García-Sanz Ramón R Ocio Enrique M EM Oriol Albert A Gironella Mercedes M Palomera Luis L De Arriba Felipe F Gonzalez Yolanda Y Johnson Sarah K SK Epstein Joshua J Barlogie Bart B Lahuerta Juan José JJ Blade Joan J Orfao Alberto A Mateos María-Victoria MV San Miguel Jesús F JF

Blood 20160111 15

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 sho ...[more]

PMID: 26755711

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Project description:Immunoglobulin light-chain amyloidosis (AL) is a rare clonal plasma cell (PC) disorder that remains largely incurable. AL and multiple myeloma (MM) share the same cellular origin, but while knowledge about MM PC biology has improved significantly, the same does not apply for AL. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 22 newly-diagnosed AL patients. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and MGUS or MM patients. However, in contrast to MM, highly-purified FACSs-sorted clonal PCs in AL (n=9/22) show virtually normal transcriptomes with only 68 deregulated genes as compared to normal PCs, including a few tumor suppressor (CDH1, RCAN) and pro-apoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11/22) were genomically unstable with a median of 9 copy-number-abnormities (CNAs) per case; many of which similar to those found in MM. Whole-exome sequencing (WES) was performed in three AL patients and revealed a median of 10 non-recurrent mutations per case. Altogether, we showed that although clonal PCs in AL display phenotypic and CNA profiles similar to MM, their transcriptome is remarkably similar to that of normal PCs. First-ever WES revealed the lack of a unifying mutation in AL A total of 22 patients with confirmed diagnosis of AL based on the presence of amyloid-related systemic syndrome, positive amyloid tissue staining with Congo red, and evidence of PC clonality were studied. Samples were collected after informed consent was given, in accordance with local ethical committee guidelines and the Helsinki Declaration. GEP was performed in 9/22 AL cases with adequate RNA extracted from FACS-purified clonal PCs according to patient-specific aberrant phenotypes, and compared to that of normal PCs from 5 healthy individuals (FACSAriaIIb, BDB; â¥95% purity). RNA was hybridized to the Human Gene 1.0 ST Array (Affymetrix, Santa Clara, CA, USA) and normalization was carried using the expression console (Affymetrix) with the RMA algorithm which includes background correction, normalization and calculation of expression values (log2). Differentially expressed genes between classes were identified using the Significant Analysis of Microarrays (SAM) algorithm (http://www-stat.standford.edu/-tibs/SAM), and significant genes were selected based on the lowest q-value (<10-5).

Project description:Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described more than 30 years ago, the phenotype of MM-CSC is still a matter of debate, especially with respect to the expression of syndecan- 1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95-99%) and CD138low (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 surface expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are also phenotypically interconvertible. Overall, our results differ from previously published data which attribute a B-cell phenotype to MM-CSC and urge the need to explore more reliable markers to discriminate true clonogenic myeloma cells. To compare the gene expression profile of the subpopulations CD138++ and CD138low within the MM cell line, RPMI-8226. RNA was isolated from CD138++ (n=3) and CD138low (n=3) RPMI-8226 cells. RNA was hybridized to Human Gene 1.0 ST array (Affymetrix) according to Affymetrix protocols [Gutierrez, 2005, 402]. Microarray data were normalized using the Robust Multichip Analysis (RMA) algorithm implemented in the Affymetrix Expression Console. Data analysis was carried out using DNA-Chip Analyzer software (DChip). The comparison criteria used in DChip analysis were fold change E/BM-bM-^IM-%2 or B/EM-bM-^IM-%2, mean difference E-B>100 or B-E>100 and the lower 90% confidence bound of fold-change was used

Dataset Information

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

Publications

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

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