Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-β

Abstract

Primary myelofibrosis (PMF) is a Philadelphia chromosome negative myeloproliferative neoplasm (MPN) with adverse prognosis and is associated with bone marrow fibrosis and extramedullary hematopoiesis. Even though the discovery of the Janus kinase 2 (JAK2), thrombopoietin receptor (MPL) and calreticulin (CALR) mutations have brought new insights into the complex pathogenesis of MPNs, the etiology of fibrosis is not well understood. Furthermore, since JAK2 inhibitors do not lead to reversal of fibrosis further understanding of the biology of fibrotic process is needed for future therapeutic discovery. Transforming growth factor beta (TGF-β) is implicated as an important cytokine in pathogenesis of bone marrow fibrosis. Various mouse models have been developed and have established the role of TGF-β in the pathogenesis of fibrosis. Understanding the molecular alterations that lead to TGF-β mediated effects on bone marrow microenvironment can uncover newer therapeutic targets against myelofibrosis. Inhibition of the TGF-β pathway in conjunction with other therapies might prove useful in the reversal of bone marrow fibrosis in PMF.

Keywords: GATA-1; Primary myelofibrosis (PMF); thrombopoietin (TPO); transforming growth factor beta 1 (TGF-β1).

Figure 1

Classification of myeloproliferative neoplasm. Others include chronic neutrophilic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, MPNs, unclassifiable. PV, polycythemia vera; ET, essential thrombocytosis; PMF, primary myelofibrosis; JAK2, Janus kinase 2; MPL, thrombopoietin receptor; CALR, calreticulin.

Figure 2

Pathogenesis of fibrosis: constitutive activation of JAK-STAT pathway in the MPN stem cell cohort leads to cytokine independent growth of megakaryocytes. Emperipolesis of neutrophils occurs that leads to release of TGF-β, PDGF and bFGF from alpha granules present in megakaryocytes. These cytokines cause fibrosis and angiogenesis and also lead to osteosclerosis by causing the stromal cells to release osteoprotegerin. MPN, myeloproliferative neoplasm; TGF-β, transforming growth factor beta; PDGF, platelet derived growth factor; FGF, basic fibroblast growth factor.

Figure 3

Transforming growth factor beta signaling pathway TGFβ1 latent proteins are present in 2 forms; a small complex consists of TGF-β noncovalently associated with a latency-associated protein (LAP) and a large latent complex in which LAP is linked to latent TGF-β-binding proteins (LTBPs). Integrins, plasmin and thrombospondin 1 (TSP-1) convert the inactive latent complex to the active form by releasing it from LTBP and LAP. The active TGF-β I binds to the type II receptor (TRII) which then recruits, transphosphorylates and binds the type I receptor (TRI). The activated TRI phosphorylates the transcription factors R-Smads (Smad 2/3) which then bind to the common Smad 4. R-Smad/Co-Smad complexes translocate to the nucleus, where they associate with DNA-binding partners and then regulate the transcriptional response of the TGF- β target genes. Inhibitory Smad 6 and 7 repress TGF-β responses.