title: Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies.
abstract: Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen in a variety of malignant and non-malignant disease states, the deposition of reticulin and collagen fibrosis in the bone marrow of patients with myelofibrosis is believed to be mediated by the myelofibrosis hematopoietic stem/progenitor cell, contributing to an impaired microenvironment favoring malignant over normal hematopoiesis. Increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling have all been implicated in the pathogenesis of bone marrow fibrosis. A number of studies indicate that bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms. However, modern myelofibrosis prognostication systems utilized in risk-adapted treatment approaches do not include bone marrow fibrosis as a prognostic variable. The specific effect on bone marrow fibrosis of JAK2 inhibition, and other rationally based therapies currently being evaluated in myelofibrosis, has yet to be fully elucidated. Hematopoietic stem cell transplantation remains the only curative therapeutic approach that reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis. Here we review the pathogenesis, biological consequences, and prognostic impact of bone marrow fibrosis. We discuss the rationale of various anti-fibrogenic treatment strategies targeting the clonal hematopoietic stem/progenitor cell, aberrant signaling pathways, fibrogenic cytokines, and the tumor microenvironment.
authors.affiliation: Division of Hematology Oncology, Mount Sinai Beth Israel, New York, NY, USA.
authors.forename: Abdallah Abou
authors.initials: AA
authors.lastname: Zahr
authors.affiliation: Associated Regional University Pathologists Laboratories, Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Salama
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Carreau
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Tremblay
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Mesa
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA john.mascarenhas@mssm.edu.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D060833:Cellular Microenvironment; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D055728:Primary Myelofibrosis / Q000175:diagnosis* / Q000209:etiology* / Q000628:therapy*; D011379:Prognosis; D012720:Severity of Illness Index