title: Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma.
abstract: Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.
authors.affiliation: Institut Pasteur de Tunis, Laboratory of Clinical Immunology, Tunis, Tunisia.
authors.forename: Asma
authors.identifier: http://orcid.org/0000-0002-7806-9687
authors.initials: A
authors.lastname: Beldi-Ferchiou
authors.affiliation: Institut Pasteur de Tunis, Laboratory of Clinical Immunology, Tunis, Tunisia.
authors.forename: Nour
authors.initials: N
authors.lastname: Skouri
authors.affiliation: Institut Pasteur de Tunis, Laboratory of Clinical Immunology, Tunis, Tunisia.
authors.forename: Cyrine
authors.initials: C
authors.lastname: Ben Ali
authors.affiliation: Institut Pasteur de Tunis, Laboratory of Molecular and Cellular Hematology, Tunis, Tunisia.|Université de Tunis El Manar, Faculté de Médecine de Tunis, Tunis, Tunisie.
authors.forename: Ines
authors.initials: I
authors.lastname: Safra
authors.affiliation: Bone Marrow Transplantation Center, Tunis, Tunisia.
authors.forename: Abderrahman
authors.initials: A
authors.lastname: Abdelkefi
authors.affiliation: Université de Tunis El Manar, Faculté de Médecine de Tunis, Tunis, Tunisie.|Bone Marrow Transplantation Center, Tunis, Tunisia.
authors.forename: Saloua
authors.initials: S
authors.lastname: Ladeb
authors.affiliation: Université de Tunis El Manar, Faculté de Médecine de Tunis, Tunis, Tunisie.|Salah Azaiez Institute, Department of Pathology, Tunis, Tunisia.
authors.forename: Karima
authors.initials: K
authors.lastname: Mrad
authors.affiliation: Université de Tunis El Manar, Faculté de Médecine de Tunis, Tunis, Tunisie.|Bone Marrow Transplantation Center, Tunis, Tunisia.
authors.forename: Tarek
authors.initials: T
authors.lastname: Ben Othman
authors.affiliation: Institut Pasteur de Tunis, Laboratory of Clinical Immunology, Tunis, Tunisia.|Université de Tunis El Manar, Faculté de Médecine de Tunis, Tunis, Tunisie.
authors.forename: Mélika
authors.initials: M
authors.lastname: Ben Ahmed
mesh_terms: D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011446:Prospective Studies; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D012333:RNA, Messenger; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6