title: KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression.
abstract: Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Andres C
authors.initials: AC
authors.lastname: Garcia-Montero
authors.affiliation: Servicio de Secuenciación de ADN, Centro de Investigación del Cáncer (Instituto de Biología Molecular y Celular del Cancer-Consejo Superior de Investigaciones Científicas [IBMCC-CSIC]/Universidad de Salamanca [USAL] and Institute of Biomedical Research of Salamanca [IBSAL]) and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain;
authors.forename: Maria
authors.initials: M
authors.lastname: Jara-Acevedo
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; and.
authors.forename: Ivan
authors.initials: I
authors.lastname: Alvarez-Twose
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teodosio
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Sanchez-Muñoz
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Carmen
authors.initials: C
authors.lastname: Muñiz
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Javier I
authors.initials: JI
authors.lastname: Muñoz-Gonzalez
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mayado
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; and.
authors.forename: Almudena
authors.initials: A
authors.lastname: Matito
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Carolina
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; and.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Morgado
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Luis
authors.initials: L
authors.lastname: Escribano
authors.affiliation: Servicio General de Citometría (NUCLEUS) and.
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D034721:Mastocytosis, Systemic / Q000235:genetics* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D020125:Mutation, Missense; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D014633:Valine / Q000235:genetics
chemical_list: D001224:Aspartic Acid; D019009:Proto-Oncogene Proteins c-kit; D014633:Valine