Research Themes
The original concept proposed by our research team is that for subsets of patients, inflammation in response to latent infection or as a consequence of genetic defects (in JAK2, CALR, MPL, and oxygen-sensing genes) may lead to chronic hematologic malignancy such as myeloproliferative neoplasms (MPN) and multiple myeloma (MM).
Our aim is to provide evidence that inflammation is an early event in the pathogenesis of MM or MPN, which facilitates acquisition of alterations in genes that regulate lymphoid or myeloid cell physiology (in MPN: JAK2, CALR, MPL mutation), especially if the host immune response to inflammation is abnormal. During the 2010-2014 period, we showed that inflammatory cytokines fuel the proliferation of MPN clones independently of JAK2V617F, the main MPN mutation (Oncogene 2011; Haematologica 2011) and that the JAK2V617F mutation is not sufficient to explain the complexity of MPN diseases ((Boissinot et al., Oncogene 2011 ; Vilaine et al., Blood 2011 ; Lippert et al., Haematologica 2014). We also provided evidence of latent infection in monoclonal gammopathies of undetermined significance (MGUS) and multiple myeloma (MM): for 25% of MGUS/MM patients, the purified monoclonal immunoglobulin (mc Ig) recognizes an antigen from one of the following pathogens: Epstein-Barr virus (EBV), hepatitis C virus (HCV) or Helicobacter pylori (H. pylori) (Hermouet et al., New Engl J Med 2003; Bigot-Corbel et al., Blood 2008; Feron et al., Analytical Biochem 2013; Bosseboeuf et al., J Clin Invest Insight 2017; Bosseboeuf et al., Frontiers Immunology).
Team 16 now studies two mechanisms of chronic inflammation:
1) Genetic alterations related to inflammation, inflammatory cytokines, their production and their signaling pathways. We aim to determine the cytokine profile of patients diagnosed with MPN and related diseases; the dependence on mutations (JAK2, MPL, CALR mutations) of cytokines identified as strongly deregulated in specific subsets of patients; the causes of deregulation of inflammation cytokines produced independently of JAK2, MPL, CALR mutations.
2) Latent infection and chronic infectious antigenic stimulation of hematopoietic cells, as pre-disposition to malignant transformation, as described for EBV, HCV and H. pylori in MGUS and in MM. We also aim to identify new infectious agents associated with MGUS, MM or MPN, and improve understanding of the immune and inflammatory response to infection in MGUS, MM, or MPN.
Team
Sylvie Hermouet, MCU-PH, University of Nantes
Edith Bigot-Corbel, MCU-PH, University of Nantes
Jean Harb, MCU-PH, University of Nantes
Sophie Allain-Maillet, Engineer Inserm
Nicolas Mennesson, Engineer
Margaux Louvois, Master 2 Student EPHE
Seven representative publications
1. Roy R, Ang E, Komatsu E, et al. Absolute quantitation of glycoforms of two human IgG subclasses using synthetic Fc peptides and glycopeptides. J Am Soc Mass Spectrometry
http://www.hal.inserm.fr/inserm-01806658
2. Bosseboeuf A, Feron D, Tallet A, et al. Monoclonal IgG in MGUS and multiple myeloma target infectious pathogens. J Clin Invest Insight (2017)
http://www.hal.inserm.fr/inserm-01628286v1
3. Bosseboeuf A, Allain S, Mennesson N, et al. Pro-inflammatory state in MGUS and Myeloma is characterized by low sialylation of pathogen-specific and other monoclonal and polyclonal immunoglobulin G. Frontiers Immunology (2017)
http://www.hal.inserm.fr/inserm-01628293v1
4. Cleyrat C, Girard R, Choi EH, et al. Gene Editing Rescue of a Novel MPL Mutant Associated with Congenital Amegakaryocytic Thrombocytopenia. Blood Advances (2017)
http://www.hal.inserm.fr/inserm-01595962v1
5. Sylvie Hermouet. Pathogenesis of myeloproliferative neoplasms: More than mutations. Experimental Hematology (2015)
http://www.hal.inserm.fr/inserm-01402448
6. Hermouet S, Bigot-Corbel E, Gardie B. Pathogenesis of myeloproliferative neoplasms: Role and mechanisms of chronic inflammation. Mediators of Inflammation (2015)
http://www.hal.inserm.fr/inserm-01402440
7. Feron D, Charlier C, Gourain V et al. Multiplexed infectious protein microarray immunoassay suitable for the study of the specificity of monoclonal immunoglobulins. Analytical Biochemistry (2013)
http://www.hal.inserm.fr/inserm-01401584
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