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Pathophysiology of Myelofibrosis (MF)

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by clonal proliferation of hematopoietic stem cells (HSCs), resulting in atypical megakaryocytic hyperplasia, progressive bone marrow fibrosis, and ineffective hematopoiesis.Passamonti F et al. Crit Rev Oncol Hematol. 2022;180:103862. Garmezy B et al. Blood Rev. 2021;45:100691.

Primary MF (PMF) is 1 of 3 distinct classical MPNs (BCR-ABL1–negative), in addition to polycythemia vera (PV) and essential thrombocythemia (ET). Compared to other classical MPNs, PMF is a more heterogeneous disorder in both its clinical and biological characteristics.Vainchenker W et al. Blood. 2017;129(6):667-679. Shantzer L et al. Ann Hematol. 2017;96:531-535.

  • PMF accounts for ~68% of all MF cases and occurs de novo, whereas secondary MF arises from preexisting MPNs and is less commonGeyer HL et al. Haematologica. 2017;102(1):85-93.
  • MF is defined by progressive bone marrow fibrosis resulting from a nonclonal fibroblastic response to cytokines produced by aberrant clonal myeloid cells, primarily megakaryocytesNaymagon L et al. Hemasphere. 2017;1(1):e1.

The development of anemia in MF is a multifactorial process driven by fibrosis of the bone marrow and displacement of hematopoietic progenitor cells to extramedullary sites.Passamonti F et al. Crit Rev Oncol Hematol. 2022;180:103862. Naymagon L et al. Hemasphere. 2017;1(1):e1.

  • In some instances, anemia can develop as a result of MF treatmentNaymagon L et al. Hemasphere. 2017;1(1):e1.

Patients with MF are also at risk for acute myeloid leukemia (AML) transformation. Approximately 10%-20% of patients with MF will develop AML within 10 years of diagnosis.Garmezy B et al. Blood Rev. 2021;45:100691.

Bone marrow fibrosis and anemia in MFPassamonti F et al. Crit Rev Oncol Hematol. 2022;180:103862. Garmezy B et al. Blood Rev. 2021;45:100691. Shantzer L et al. Ann Hematol. 2017;96:531-535. Naymagon L et al. Hemasphere. 2017;1(1):e1. Tefferi A et al. Haematologica. 2023;108(11):2919-2932

Genetic abnormalities that cause dysregulation of the janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling pathway lead to changes in cytokine and growth factor expression, which promote inflammation and fibrosis within the bone marrow.

Fibrosis of the bone marrow and a proinflammatory microenvironment leads to impaired iron metabolism and disrupted erythroid differentiation. This impedes effective hematopoiesis including the production of mature red blood cells (RBCs), contributing to the development of anemia.

Insufficient hematopoiesis in the bone marrow drives the displacement of HSCs from the bone marrow to extramedullary sites outside the marrow, such as the spleen and liver. Enlargement of the spleen (splenomegaly) due to extramedullary erythropoiesis results in increased plasma volume and sequestration and destruction of circulating RBCs, further worsening anemia.

Treatment with JAK inhibitors (JAKis) has been shown to reduce spleen size and improve symptom burden in patients with MF. However, in some cases, they may cause or worsen anemia via suppression of residual marrow function.

Abnormalities and mutations

Multiple chromosomal abnormalities and genetic mutations have been associated with the development of MFGarmezy B et al. Blood Rev. 2021;45:100691.

To learn more, view the tabs below. Each tab contains helpful information.

Cytogenetic abnormalities in MFTefferi A et al. Leukemia. 2018;32(5):1189-1199.a

Adapted from Leukemia.Tefferi A et al. Leukemia. 2018;32(5):1189-1199.
mOS, median overall survival; VHR, very high risk; y, years.
aA study of 1,002 patients with primary myelofibrosis.

  • Karyotypic abnormalities are seen in ~40%-45% of patients with PMF and are more commonly used for determining prognosis and treatment decisionsGarmezy B et al. Blood Rev. 2021;45:100691. Shao R et al. Cancers (Basel). 2025;18(1):50.
  • The most common chromosomal abnormalities include del(20q), del(13q), trisomy 8, and trisomy 9Garmezy B et al. Blood Rev. 2021;45:100691. Shao R et al. Cancers (Basel). 2025;18(1):50.

Somatic mutations

Adapted from Curr Hematol Malig Rep.Thaw K et al. Curr Hematol Malig Rep. 2024;19(6):264-275.

  • Somatic mutations in PMF are categorized as driver mutations, which occur in genes such as JAK2, MPL, and CALR, and nondriver mutations, including ASXL1, SRSF2, IDH1, IDH2, and othersGarmezy B et al. Blood Rev. 2021;45:100691. Shao R et al. Cancers (Basel). 2025;18(1):50.
  • JAK2, MPL, and CALR mutations occur in more than 90% of patients with PMF (occurring in ~50%–60%, ~30%, and ~5%–10% of cases, respectively) and are usually, but not always, mutually exclusiveGarmezy B et al. Blood Rev. 2021;45:100691. Shao R et al. Cancers (Basel). 2025;18(1):50.
  • Approximately 5% of PMF cases are “triple negative” without known driver mutationsGarmezy B et al. Blood Rev. 2021;45:100691. Shao R et al. Cancers (Basel). 2025;18(1):50.
    • Triple-negative MF is associated with poor prognosisGarmezy B et al. Blood Rev. 2021;45:100691. Shao R et al. Cancers (Basel). 2025;18(1):50.

Frequency of driver mutations

Adapted from Blood Rev and Cancers.Garmezy B et al. Blood Rev. 2021;45:100691.

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References

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