title: Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis.
abstract: The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB,and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis.
authors.affiliation: Department of Hematology, Hospital Universitario de León, León, Spain.|Instituto de Biomedicina (IBIOMED), Universidad de León, León, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, IBSAL, IBMCC-Centro de Investigación del Cáncer (USAL-CSIC), Salamanca, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Robledo
authors.affiliation: Department of Pathology, Hospital Universitario de León, León, Spain.
authors.forename: Francisco Miguel
authors.initials: FM
authors.lastname: Izquierdo-García
authors.affiliation: Department of Pathology, Hospital Valle del Nalón, Langreo-Asturias, Spain.
authors.forename: Dimas
authors.initials: D
authors.lastname: Suárez-Vilela
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, IBSAL, IBMCC-Centro de Investigación del Cáncer (USAL-CSIC), Salamanca, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Benito
authors.affiliation: Department of Hematology, Hospital Universitario de León, León, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Fuertes
authors.affiliation: Department of Hematology, Hospital Universitario U. Marqués de Valdecilla, Santander, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Insunza
authors.affiliation: Department of Molecular Pathology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Barragán
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, IBSAL, IBMCC-Centro de Investigación del Cáncer (USAL-CSIC), Salamanca, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Del Rey
authors.affiliation: Department of Immunology, Hospital Universitario de León, León, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: García-Ruiz de Morales
authors.affiliation: Department of Hematology-Oncology, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Tormo
authors.affiliation: Department of Hematology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.affiliation: Unit of Molecular Genetics, ICO-Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras, Badalona, Spain.
authors.forename: Lurdes
authors.initials: L
authors.lastname: Zamora
authors.affiliation: Department of Hematology, Hospital del Mar, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pedro
authors.affiliation: Department of Hematology, Hospital Universitario de León, León, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sánchez-Del-Real
authors.affiliation: Department of Hematology, Hospital Universitario de Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Díez-Campelo
authors.affiliation: Department of Hematology, Hospital Universitario de Salamanca, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Del Cañizo
authors.affiliation: Department of Hematology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
authors.forename: Guillermo F
authors.initials: GF
authors.lastname: Sanz
authors.affiliation: Unidad de Diagnóstico Molecular y Celular del Cáncer, IBSAL, IBMCC-Centro de Investigación del Cáncer (USAL-CSIC), Salamanca, Spain.|Department of Hematology, Hospital Universitario de Salamanca, Spain.
authors.forename: Jesús María
authors.initials: JM
authors.lastname: Hernández-Rivas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D054357:Chemokine CXCL10 / Q000097:blood; D054370:Chemokine CXCL9 / Q000097:blood; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D016159:Tumor Suppressor Protein p53; D025721:WT1 Proteins; C583751:WT1 protein, human
keywords: bone marrow fibrosis; myelodysplastic syndromes; next-generation sequencing; pathogenesis; prognosis