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.

Figure 1.

Photomicrograph showing reticulin (silver) stain in a specimen from a patient with myelofibrosis. Note the diffuse and dense increase in reticulin with extensive intersections which would be graded as 2+ myelofibrosis. The left upper corner is a mark up image of post-image analysis processing with the reticulin fibers being de-convoluted from background tissue. The area occupied by the fibers, as well as branching points, could be objectively quantified using computer assisted image analysis (original magnification, 400X).

Figure 2.

Trichrome stain showing deposits of collagen fibers. The fibers are arranged in bundles that are marked with red arrows (original magnification 400X).

Figure 3.

Four images from unstained bone marrow biopsies obtained from patients with myeloproliferative neoplasms with a spectrum of marrow fibrosis ranging from 0–3 according to the revised European consensus system for grading bone marrow fibrosis. The red is a pseudo color that highlights all tissue elements in the bone marrow according to two-photon excitation. The technology utilizes the second harmonic generation phenomenon to highlight fibrillar collagen with high specificity as highlighted by the green fluorescent colored structures.