In primary myelofibrosis (PMF), megakaryocyte dysplasia/hyperplasia determines the release of inflammatory cytokines that, in turn, stimulate stromal cells and induce bone marrow fibrosis.7,9
- Aberrant megakaryocytes produce excessive fibrotic growth factors, resulting in bone marrow fibrosis and impaired hematopoiesis.
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.7
MPNs, including MF, frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2).7,10,11
- The exact etiology of MF is unknown and there are no known risk factors for the disease, although overactive Janus-associated kinase (JAK) pathway signaling is present in all patients.
- Somatic mutations PMF are classified into "driver" and "other" mutations; the former include JAK2 (~65%), CALR (~25%), and MPL (~10%) and the latter ASXL1, SRSF2, and U2AF1, among others.11
- A minority of patients do not have any of the 3 main "driver mutations" and are referred to as Triple Negative disease (10-15%).11
- The pathogenesis of MPNs is poorly understood and even though mutations in JAK2, MPL, and CALR are seen and can lead to constitutive action of the JAK-STAT pathway, it has not been elucidated how these mutations can cause different clinical phenotypes.7