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
- Development of myelofibrosis is the result of multiple genetic mutations.
- Genes involved in the pathogenesis of myelofibrosis include:[12][13][14][3][15][16][17][18][19][20]
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)
References
- ↑ 1.0 1.1 Bedekovics J, Méhes G (March 2014). "[Pathomechanism and clinical impact of myelofibrosis in neoplastic diseases of the bone marrow]". Orv Hetil (in Hungarian). 155 (10): 367–75. doi:10.1556/OH.2014.29823. PMID 24583557.
- ↑ Vainchenker W, Kralovics R (February 2017). "Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms". Blood. 129 (6): 667–679. doi:10.1182/blood-2016-10-695940. PMID 28028029.
- ↑ 3.0 3.1 3.2 Alshemmari SH, Rajan R, Emadi A (2016). "Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review". Med Princ Pract. 25 (6): 501–509. doi:10.1159/000450956. PMC 5588514. PMID 27756071.
- ↑ de Freitas RM, da Costa Maranduba CM (2015). "Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview". Rev Bras Hematol Hemoter. 37 (5): 348–53. doi:10.1016/j.bjhh.2014.10.001. PMC 4685044. PMID 26408371.
- ↑ Le Bousse-Kerdilès MC, Martyré MC (October 1999). "Dual implication of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid metaplasia with myelofibrosis". Ann. Hematol. 78 (10): 437–44. PMID 10550553.
- ↑ Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP (November 2007). "Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres". Br. J. Haematol. 139 (3): 351–62. doi:10.1111/j.1365-2141.2007.06807.x. PMID 17910625.
- ↑ Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R (December 2013). "Somatic mutations of calreticulin in myeloproliferative neoplasms". N. Engl. J. Med. 369 (25): 2379–90. doi:10.1056/NEJMoa1311347. PMID 24325356.
- ↑ 8.0 8.1 Mak YK, Chan CH, So CC, Chan MK, Chu YC (February 2002). "Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady". Clin Lab Haematol. 24 (1): 55–9. PMID 11843900.
- ↑ 9.0 9.1 Philipponnet C, Ronco P, Aniort J, Kemeny JL, Heng AE (December 2017). "Membranous Nephropathy and Intrarenal Extramedullary Hematopoiesis in a Patient With Myelofibrosis". Am. J. Kidney Dis. 70 (6): 874–877. doi:10.1053/j.ajkd.2017.06.022. PMID 28821362.
- ↑ 10.0 10.1 10.2 10.3 Yang M, Roarke M (March 2017). "Diffuse pulmonary extramedullary hematopoiesis in myelofibrosis diagnosed with technetium-99m sulfur colloid bone marrow scintigraphy and single photon emission computerized tomography/CT". Am. J. Hematol. 92 (3): 323–324. doi:10.1002/ajh.24616. PMID 27883206.
- ↑ 11.0 11.1 Pizzi M, Gergis U, Chaviano F, Orazi A (September 2016). "The effects of hematopoietic stem cell transplant on splenic extramedullary hematopoiesis in patients with myeloproliferative neoplasm-associated myelofibrosis". Hematol Oncol Stem Cell Ther. 9 (3): 96–104. doi:10.1016/j.hemonc.2016.07.002. PMID 27521149.
- ↑ Tefferi, A; Lasho, T L; Finke, C M; Knudson, R A; Ketterling, R; Hanson, C H; Maffioli, M; Caramazza, D; Passamonti, F; Pardanani, A (2014). "CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons". Leukemia. 28 (7): 1472–1477. doi:10.1038/leu.2014.3. ISSN 0887-6924.
- ↑ Baxter EJ, Scott LM, Campbell PJ; et al. (2005). "Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders". Lancet. 365 (9464): 1054–61. doi:10.1016/S0140-6736(05)71142-9. PMID 15781101.
- ↑ Pikman Y, Lee BH, Mercher T; et al. (2006). "MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia". PLoS Med. 3 (7): e270. doi:10.1371/journal.pmed.0030270. PMC 1502153. PMID 16834459. Unknown parameter
|month=ignored (help) - ↑ Shammo JM, Stein BL (December 2016). "Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions". Hematology Am Soc Hematol Educ Program. 2016 (1): 552–560. doi:10.1182/asheducation-2016.1.552. PMC 6142495. PMID 27913528.
- ↑ Li B, Xu J, Wang J, Gale RP, Xu Z, Cui Y, Yang L, Xing R, Ai X, Qin T, Zhang Y, Zhang P, Xiao Z (November 2014). "Calreticulin mutations in Chinese with primary myelofibrosis". Haematologica. 99 (11): 1697–700. doi:10.3324/haematol.2014.109249. PMC 4222480. PMID 24997152.
- ↑ Rotunno G, Pacilli A, Artusi V, Rumi E, Maffioli M, Delaini F, Brogi G, Fanelli T, Pancrazzi A, Pietra D, Bernardis I, Belotti C, Pieri L, Sant'Antonio E, Salmoiraghi S, Cilloni D, Rambaldi A, Passamonti F, Barbui T, Manfredini R, Cazzola M, Tagliafico E, Vannucchi AM, Guglielmelli P (July 2016). "Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group". Am. J. Hematol. 91 (7): 681–6. doi:10.1002/ajh.24377. PMID 27037840.
- ↑ Song J, Hussaini M, Zhang H, Shao H, Qin D, Zhang X, Ma Z, Hussnain Naqvi SM, Zhang L, Moscinski LC (May 2017). "Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis". Am. J. Clin. Pathol. 147 (5): 444–452. doi:10.1093/ajcp/aqw222. PMC 5402718. PMID 28419183.
- ↑ Tefferi A (December 2016). "Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management". Am. J. Hematol. 91 (12): 1262–1271. doi:10.1002/ajh.24592. PMID 27870387.
- ↑ Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A, Finke C, Score J, Gangat N, Mannarelli C, Ketterling RP, Rotunno G, Knudson RA, Susini MC, Laborde RR, Spolverini A, Pancrazzi A, Pieri L, Manfredini R, Tagliafico E, Zini R, Jones A, Zoi K, Reiter A, Duncombe A, Pietra D, Rumi E, Cervantes F, Barosi G, Cazzola M, Cross NC, Tefferi A (September 2013). "Mutations and prognosis in primary myelofibrosis". Leukemia. 27 (9): 1861–9. doi:10.1038/leu.2013.119. PMID 23619563.