Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis

Abstract

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine “storm” produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes “independent” of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies.

Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms

“…PDGF has long been implicated in the development of BM fibrosis in MPN along with TGF-β and bFGF (57,69,70). Mainly produced by megakaryocytes, PDGF is primarily stored and released from α granules in megakaryocytes and platelets, but production in fibroblasts, osteoblasts, and endothelial cells has also been delineated (57).…”

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

“…Its elevated levels are also characteristic for the primary myelofibrosis. 34,35 It has been proposed that CD34 C blasts are the major producers of IL8 in BM of MDS patients, 32 because the initially elevated levels of IL8 in BM serum of MDS or AML patients subsequently decrease with the complete remission and disappearance of CD34 C blasts. Later, Schinke et al detected the elevated IL8 transcripts in AML/MDS BM samples.…”

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

“…Chronic inflammation sustained by the continuous release of proinflammatory cytokines and chemokines and subsequent bone marrow microenvironment alterations are considered key factors in PMF pathogenesis. The abnormal production of cytokines that occurs both in malignant and nonmalignant cells was related to an increased JAK2-STAT3 activation and was found responsible for the inhibition of apoptosis and increased myeloproliferation, creating an environment that favors MPN clone maintenance and expansion [31,32]. Recently, it was shown that MF cells downregulated the expression of X-linked inhibitor of apoptosis (XIAP) and mitogen-activated protein kinase 8 (MAPK 8), a necessary component of TNFmediated apoptosis, via a TNF/TNFR2-dependent autocrine loop.…”