MPN promotes myelofibrosis and impairs normal HSCs via remodeling of the bone marrow niche.

  • Major finding: MPN promotes myelofibrosis and impairs normal HSCs via remodeling of the bone marrow niche.

  • Mechanism: MPN stimulates production of inflammatory osteoblastic cells from multipotent stromal cells.

  • Impact: Disruption of the crosstalk between these cells may prevent myelofibrosis and limit LSC growth.

Myeloproliferative neoplasms (MPN) such as chronic myelogenous leukemia (CML) are characterized by disruption of normal hematopoietic stem cell (HSC) function, proliferation of transformed leukemic stem cells (LSC), and progression to bone marrow myelofibrosis. Aberrant regulation of cells within the bone marrow microenvironment, including osteoblastic lineage cells (OBC) that support normal HSCs and are derived from multipotent stromal cells (MSC), also contribute to the development of myeloid malignancies, supporting the importance of functional crosstalk between leukemic and stromal cells. Using a mouse model of chronic-phase CML, Schepers and colleagues investigated the role of MPN in the regulation of the endosteal bone marrow niche and found that leukemic myeloid cells induced the expansion of OBCs and development of bone marrow fibrosis. MPN did not affect the growth of OBCs but instead was both necessary and sufficient to stimulate the osteoblastic differentiation of MSCs; this effect was dependent on direct contacts between leukemic myeloid cells and MSCs as well as the secretion of thrombopoietin, which promotes myelofibrosis, and chemokine (C-C motif) ligand 3, which modulates osteoblast differentiation, from leukemic myeloid cells. These functionally altered endosteal OBCs exhibited elevated expression of genes involved in extracellular matrix remodeling, inflammatory processes, and TGFβ signaling and decreased expression of NOTCH pathway genes compared with wild-type OBCs, suggesting that these cells directly promote bone marrow myelofibrosis. Furthermore, the expression of HSC retention factors was diminished in MPN-expanded OBCs, resulting in an impaired ability to support normal HSCs without compromising LSCs. These results identify a mechanism by which MPN reprograms the endosteal bone marrow niche to generate a supportive microenvironment that promotes LSC function and myelofibrosis and suggest that inhibition of the crosstalk between leukemic cells and MSCs may be a useful therapeutic strategy for patients with MPN.

Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M, Garg T, et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 2013 Jul 11 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013