Multiple myeloma (MM) is a malignancy characterized by neoplastic proliferation of plasma cells, with an incidence rate of about 5/100,000 in Europe. In the past decade, treatment options have dramatically expanded, with novel agents and combination regimens that have the potential to achieve deeper remission and prolong survival. Despite this, MM remains an incurable disease, accounting for poor quality of life and about 20% of deaths from hematological malignancies. Genetic events leading to transformation in MM are complex and only partially understood. During the five past years we explored the genomic landscape of myeloma cells from patients at different stages of the disease.
Our main achievements have been (1) the genomic landscape of myeloma cells, (2) the discovery of massive chromosomal rearrangements in myeloma cells indicating for few patients a catastrophe model of evolution instead of a gradual model, (3) the demonstration of the complex evolution of myeloma cells sub populations under treatment pressure providing new insights into mechanisms that drive resistance to treatment and (4) the refinement of a definition of high-risk patients based on genomic, genetic and bioclinical parameters in the context of new drugs. Although, many types of genetic lesions, including chromosomal translocations, point mutations and a variety of copy-number aberrations, have been identified in MM in the past ten years, they do not fully explain the molecular mechanisms underlying relapse and do not provide a robust risk classification for risk-adapted therapy. We hypothesize that epigenome variability could contribute to the aggressive and chemoresistant phenotype of relapsed MM. Likewise, genetic alterations in coding regions do not solely explain the oncogenic processes that shape MM transcriptome, therefore it is critical to identify altered distal regulatory elements and assign them to target genes.
Our research effort for the next five years is to (1) pursue our work on genomic landscape based on deep sequencing in collaboration with Dana Farber Cancer Institute, (2) explore epigenome variability focus on DNA methylation variability and non coding RNAs expression changes to better understand the contribution of epigenomic alterations to MM progression and relapse and (3) analyse the landscape of cis-regulatory regions and transcription factors networks changes in myeloma cells compared to their normal counterpart and over lineages to unravel how the normal gene expression program of bone marrow plasma cells are dramatically altered during transformation. Our ultimate goal is to identify and characterize tumor-promoting genetic and epigenetic changes occurring in myeloma patients during the course of the disease, in order to define a risk-adapted therapy that connects genomic and epigenomic variants to clinical phenotype.
Stéphane Minvielle, (PhD), DR1 CNRS
Aurélien Serandour (PhD), MC Centrale Nantes / Chaire Inserm
Florence Magrangeas (PhD), Autre_Ch
Philippe Moreau (MD), PUPH CHU
Loïc Campion (MD), PH ICO
Catherine Guérin-Charbonnel, IE CHU/ICO
Wilfried Gouraud, IE ICO
Magali Devic, TR ICO
Elise Douillard, TR CHU
Nathalie Roi, TR CHU
Emilie Moranton, TR ICO
Jean-Baptiste Alberge, Doctorant
Victor Gaborit, Doctorant
Jennifer Rondineau, Doctorant
Benjamin Delaune, IE CHU
Amélie Chérubin, IE Inserm
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2) Miannay B, Minvielle S, Roux O, Drouin P, Avet-Loiseau H, Guérin-Charbonnel C, Gouraud W, Attal M, Facon T, Munshi NC, Moreau P, Campion L, Magrangeas F, Guziolowski C. Logic programming reveals alteration of key transcription factors in multiple myeloma. Sci Rep. 2017 Aug 23;7(1):9257.
3) Sérandour AA, Avner S, Mahé EA, Madigou T, Guibert S, Weber M, Salbert G. Single-CpG resolution mapping of 5-hydroxymethylcytosine by chemical labeling and exonuclease digestion identifies evolutionarily unconserved CpGs as TET targets. Genome Biol. 2016 Mar 29;17:56.
4) Magrangeas F, Kuiper R, Avet-Loiseau H, Gouraud W, Guérin-Charbonnel C, Ferrer L, Aussem A, Elghazel H, Suhard J, Der Sakissian H, Attal M, Munshi NC, Sonneveld P, Dumontet C, Moreau P, van Duin M, Campion L, Minvielle S. A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma. Clin Cancer Res. 22:4350-4355, 2016.
5) Magrangeas F, Avet-Loiseau H, Gouraud W, Lodé L, Decaux O, Godmer P, Garderet L, Voillat L, Facon T, Stoppa AM, Marit G, Hulin C, Casassus P, Tiab M, Voog E, Randriamalala E, Anderson KC, Moreau P, Munshi NC, Minvielle S. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia, 27:473-481, 2013.
6) Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood, 118:67567-67568, 2011.
7) Avet-Loiseau H, Magrangeas F, Moreau P, Attal M, Facon T, Anderson KC, Harousseau JL, Munshi NC, Minvielle S. Molecular heterogeneity of multiple myeloma: pathogenesis, prognosis, and therapeutic implications. J Clin Oncol., 29:1893-1897, 2011.
8) Avet-Loiseau H, Li C, Magrangeas F, Charbonnel C, Gouraud W, Harousseau JL, Attal M, Marit G, Mathiot C, Facon T, Moreau P, Anderson K, Campion L, Munshi N, and Minvielle S. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol., 27:4585-90, 2009.
Chaire INSERM / ECN
Ligue contre le cancer
Fondation Française pour la Recherche contre le Myélome et les Gammapathies monoclonales
Intergroupe Francophone du Myélome
International Myeloma Foundation