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Myelofibrosis osteoclasts are clonal and functionally impaired

Ivo Veletic, Taghi Manshouri, Asha S. Multani, C. Cameron Yin, Lei Chen, Srdan Verstovsek and Zeev Estrov

Key points

  • Myelofibrosis osteoclasts are derived from the neoplastic clone.

  • The bone resorption capacity of myelofibrosis osteoclasts is impaired.

Abstract

Bone marrow (BM) sclerosis is commonly found in patients with late stage myelofibrosis (MF). Because osteoclasts (OC) and osteoblasts play a key role in bone remodeling, and MF monocytes, the OC precursors, are derived from the neoplastic clone, we wondered whether decreased OC numbers or impairment in their osteolytic function affects the development of osteosclerosis. Analysis of BM biopsies from 50 MF patients showed increased numbers of multinucleated tartrate-resistant acid phosphatase (TRAP)/cathepsin K-positive OC expressing phosphorylated Janus kinase (JAK)-2. Randomly microdissected TRAP+ OC from 16 MF patients harbored JAK2 or calreticulin (CALR) mutations, confirming that MF OC are clonal. To study OC function, CD14+ monocytes from MF patients and healthy individuals were cultured and differentiated into OC. Unlike normal OC, MF OC appeared small, round with few protrusions, carried the neoplastic clones' mutations and chromosomal abnormalities. In addition, MF OC lacked F-actin-rich ring-like structures, had fewer nuclei and reduced co-localization signals, compatible with decreased fusion events, and their mineral resorption capacity was significantly reduced indicating impaired osteolytic function. Taken together, our data suggest that, although the numbers of MF OC are increased, their impaired osteolytic activity distorts bone remodeling and contributes to the induction of osteosclerosis.

  • Submitted October 5, 2018.
  • Accepted February 6, 2019.