Myelofibrosis (MF) is a rare myeloproliferative disorder of hematopoietic stem cells that is characterized by fibrotic scarring within the bone marrow.1

Genetic mutations in JAK2 (50%), CALR (20%), and MPL (10%) account for most cases of primary MF; however, the underlying cause of the genetic mutations within hematopoietic stem cells is unknown.1

Significant efforts to identify the causes of genetic mutations within hematopoietic stem cells have led to the identification of several risk factors for the development of both primary and secondary MF.

Risk Factors of Age 

Although MF can affect people of any age, it primarily occurs in adults older than 50 years.2 The median age at diagnosis is approximately 65 years.1 When primary MF affects children, it frequently develops before they are 3 years old.1

Read more about MF epidemiology

Risk Factors of Sex 

In adults, MF occurs equally in men and women. In children, MF affects girls twice as often as boys.1

Risk Factors of Environmental Exposures

It has been reported that myeloproliferative neoplasms develop more frequently following environmental or industrial exposures to toxic substances, including benzene, fluoride, phosphorus, and toluene,1,2 and that the stimulation of erythropoietic progenitor cells and independent cytokine growth is greater in individuals with daily exposure to low concentrations of benzene than in individuals who do not have such exposure.3

In contrast, a systematic review of the literature published in 2021 reported that multiple studies suggested no significant association between benzene exposure and risk for the development of myeloproliferative neoplasms such as MF.4-6 

Although one of these studies found no significant association between low levels of exposure to benzene and risk for MF, it did suggest the plausibility of the idea that prolonged cumulative exposure to benzene over a period of 2 to 20 years could lead to the development of a myeloproliferative neoplasm such as MF.6 

Exposure to high levels of radiation may also increase the risk for MF.2

Read more about MF prognosis

Risk Factors From Comorbidities

Other Blood Disorders

Secondary MF may develop in a small number of patients with essential thrombocythemia (ET) or polycythemia vera (PV).2 Other blood or bone marrow disorders associated with secondary MF include multiple myeloma and chronic myeloid leukemia.1

In a literature review conducted in 2015, risk factors for the progression of PV to secondary MF included advanced age, leukocytosis, increased JAK2 V617F allele burden, splenomegaly, and reticulin fibrosis. Risk factors for the progression of ET to secondary MF included advanced age, splenomegaly, reticulin fibrosis, anemia, leukocytosis, absence of JAK2 V617F mutation, presence of ASXL1 mutation, and use of anagrelide. Overall, the transformation of ET or PV to secondary MF worsens the prognosis and makes disease management more challenging.7

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Metastatic Cancers

Secondary MF may develop when primary cancers metastasize to the bone marrow, particularly primary tumors of the breasts, prostate, lungs, kidneys, adrenal glands, or thyroid gland.1

Other Disorders

Secondary MF may develop following infection with human immunodeficiency virus (HIV) or tuberculosis, or as a result of an underlying systemic disorder such as systemic sclerosis, systemic lupus erythematosus, or pulmonary hypertension.8 

Read more about MF comorbidities

Risk Factors From Lifestyle Factors


The risk for myeloproliferative neoplasms (especially ET and PV) associated with a history of smoking is 73% greater than the risk for chronic lymphocytic leukemia associated with a history of smoking, especially in women. Smoking increases the levels of inflammatory biomarkers such as C-reactive protein, leukocytes, albumin, fibrinogen, haptoglobin, and fibrin D-dimer, as well as the erythrocyte sedimentation rate.4

Research suggests that inflammatory cytokines contribute to the phenotypic transformation of PV or ET to secondary MF as well as to the development of primary MF. It is suspected that transforming growth factor-beta (TGF-β) and other cytokines produced due to hyperactivated JAK2 kinases mediate bone marrow fibrosis to a significant extent, whereas other cytokines promote extramedullary hematopoiesis. Elevated interleukin 8 and CXC motif chemokine ligand 8 (CXCL8) levels as well as hyperactivated NFκB pathway signaling in a pan-hematopoietic pattern can promote the transformation of MF to secondary acute myeloid leukemia.9

Read more about MF pathophysiology


A high body mass index (BMI) increases risk for ET, but not PV.4,10 Both ET and PV are risk factors for secondary MF. Further investigation is required to establish the link between obesity and the development of myeloproliferative diseases.4 

Read more about MF etiology

Risk Factors of Race/Ethnicity

Research indicates that incidence of myeloproliferative disorders, including MF, is increased among Ashkenazi Jews.11,12 

Read more about MF genetics


  1. Primary myelofibrosis. NORD. Accessed December 13, 2022.
  2. Myelofibrosis. Mayo Clinic. Accessed December 13, 2022.
  3. Allahverdi N, Yassin M, Ibrahim M. Environmental factors, lifestyle risk factors, and host characteristics associated with Philadelphia negative myeloproliferative neoplasm: a systematic review. Cancer Control. 2021;28:10732748211046802. doi:10.1177/10732748211046802
  4. Smith MT. Advances in understanding benzene health effects and susceptibility. Annu Rev Public Health. 2010;31:133-148. doi:10.1146/annurev.publhealth.012809.103646
  5. Heavner K, Gross-Davis CA, Frank AL, Newschaffer C, Klotz J, Burstyn I. Working environment and myeloproliferative neoplasm: a population–based case-control study following a cluster investigation. Am J Ind Med. 2015;58(6):595-604. doi:10.1002/ajim.22451
  6. Glass DC, Schnatter AR, Tang G, Irons RD, Rushton L. Risk of myeloproliferative disease and chronic myeloid leukaemia following exposure to low-level benzene in a nested case–control study of petroleum workers. Occup Environ Med. 2014;71(4):266-274. doi:10.1136/oemed-2013-101664
  7. Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5(11):e366. doi:10.1038/bcj.2015.95
  8. Liesveld J. Myelofibrosis. Merck Manual Consumer Version. Updated September 2022. Accessed December 13, 2022.
  9. Fisher DAC, Fowles JS, Zhou A, Oh ST. Inflammatory pathophysiology as a contributor to myeloproliferative neoplasms. Front Immunol. 2021;12:683401. doi:10.3389/fimmu.2021.683401
  10. Leal AD, Thompson CA, Wang AH, et al. Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in The Iowa Women’s Health Study (IWHS) cohort. Int J Cancer. 2014;134(7):1741-1750. doi:10.1002/ijc.28492
  11. Chaiter Y, Brenner B, Aghai E, Tatarsky I. High incidence of myeloproliferative disorders in Ashkenazi Jews in northern Israel. Leuk Lymphoma. 1992;7(3):251-255. doi:10.3109/10428199209053630
  12. Myelofibrosis. Mount Sinai. Accessed December 13, 2022.

Reviewed by Debjyoti Talukdar, MD, on 12/31/2022.