Myelofibrosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Sujit Routray, M.D. [3]

Overview

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosis resulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis. It can mainly be associated with somatic mutation of the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult.

Pathogenesis

  • Polyclonal mesenchymal cells of the bone marrow such as, fibroblasts, osteoblasts, pericytes, endothelial cells, adipocytes, and reticular cells create a functional microenvironment, which maintains hematopoiesis. This maintenance takes place through cellular interactions via growth factors, adhesion molecules, cytokines, and extracellular matrix components along with the help of oxygen and calcium.[1]
  • Myelofibrosis is the result of pathologic interaction between hematopoietic progenitor and stromal cells leading to the activation and expansion of the stroma and the accumulation of reticulin and collagen fibers produced by mesenchymal cells.[1]
  • The development and progression of myelofibrosis involves the activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, which paves the way for the overproduction of abnormal megakaryocytes.[2][3][4]
  • The abnormally proliferated megakaryocytes produce cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta, and basic fibroblast growth factor (bFGF) which are involved in the abnormal proliferation of fibroblasts, resulting in fibrosis.[5][6]
  • Myelofibrosis can result in the setting of somatic mutations in specific genes or it can also be secondary to other primary disorders.
  • The somatic mutations driving the disorder can mainly involve the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene.[3][7]
  • The fibrosis of bone marrow leads to extramedullary hematopoiesis involving the reticuloendothelial organs such as the liver and spleen. Rarely, the extramedullary hematopoiesis can also involve ectopic hematopoietic tissue which includes the skin, lymph nodes, lungs, gastrointestinal tract, peritoneum, central nervous system, and genital and urinary tracts.[8][9][10][10][11]

Sites of Extramedullary Hematopoiesis

  • The main sites of extramedullary hematopoiesis include the reticuloendothelial organs, the spleen and liver.[8][9][10][10][11]
  • Hematopoiesis can rarely also occur in the following locations:
  • Genitourinary tract
  • Central nervous system
  • Lymph nodes
  • Skin
  • Peritoneum
  • Gastroentestinal tract
  • Lungs

Genetics

Most commonly involved

  • Janus-kinase 2 (JAK2)
  • Calreticulin (CALR)
  • Myeloproliferative leukemia virus (MPL) oncogene
  • These mutations are found in approximately 90% of the patients.

Less commonly involved

  • Additional sex combs-like 1 (ASXL1)
  • Slicing factor, serine/arginine-rich 2 (SRSF2)
  • Enhancer of zeste, drosophila, homolog 2 (EZH2)

Associated Conditions

  • Myelofibrosis belongs to a group of disorders collectively called myeloproliferative disorders. Other members of this group include chronic myelogenous leukemia (CML), polycythemia vera (PV), and essential thrombocythemia (ET).
  • Myelofibrosis can be associated with a variety of medical conditions such as:
  • Malignancies and hematologic disorders (Hodgkin lymphoma, non-Hodgkin lymphoma, essential thrombocythemia, polycythemia vera, multiple myeloma, and malignancies with metastases to the bone)[22][23][24][25][26][27][28][29][30][31][32]
  • Infections (tuberculosis [TB], HIV infection, and dengue fever)[33][34][35][36]
  • Autoimmune diseases (systemic lupus erythematosus [SLE], multiple sclerosis [MS], Sjogren's syndrome, and juvenile idiopathic arthritis)[37][38][39][40]

Gross Pathology

  • On gross pathology, pancytopenia and extramedullary hematopoiesis are the characteristic findings. These are manifested as anemia, susceptibility to various infections, hapatomegaly, and splenomegaly.[41][42][43][44]

References

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