Myelofibrosis (MF)

Myelofibrosis (MF), one of the 3 classic myeloproliferative neoplasms, is characterized by an accumulation of fibrotic scar tissue in the bone marrow, which interferes with the normal production of blood cells such as erythrocytes, platelets, and leukocytes. A specific cause of primary myelofibrosis has yet to be discovered, but factors such as genetic mutations have been linked to causation. Secondary MF develops in association with another disorder, such as polycythemia vera and essential thrombocythemia. The etiology is more clear, as it is often diagnosed in relation to an accompanying disease.^1,2

Genetic Mutations

Genetic mutations acquired after birth in multipotent hematopoietic stem cells contribute to the development of most cases of primary MF.^1,3 The 4 main genetic drivers for MF are somatic mutations in the JAK2, CALR, MPL, and TET2 genes. The TET2 gene encodes for a protein whose function is unknown, while JAK2 and MPL genes encode for proteins that promote the proliferation of blood cells. The CALR gene encodes for a protein that ensures proper folding of newly formed proteins and maintains correct calcium levels within cells.^1,4

Additionally, mutations in other epigenetic regulator genes may predispose individuals to acquire somatic mutations, especially in the JAK2 gene.^4,5

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The JAK/STAT Signaling Pathway

The mutant genes encode abnormal proteins that disrupt cellular regulation. One affected pathway is the JAK/STAT signaling pathway, which is responsible for the proliferation of blood cells, especially megakaryocytes, in the bone marrow.¹ 

In MF, overactivation of the JAK/STAT signaling pathway results in clonal megakaryocytic hyperplasia.^1,3 To support their growth, the clonal megakaryocytes shed growth factors that promote nonclonal fibroblast proliferation and hyperactivity, which result in excessive reticulin and collagen fiber deposition within the bone marrow.^1,3 Excessive collagen deposition causes the hallmark characteristic of MF: fibrosis, or the accumulation of scar tissue within the bone marrow.¹

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Disruption of Hematopoiesis

Bone marrow fibrosis disrupts the normal production of blood cells. As a result, severe anemia, leukopenia/leukocytosis, and thrombocytopenia/thrombocytosis cause the various signs and symptoms of MF.¹

To compensate for the lack of hematopoiesis in the bone marrow, the liver and spleen produce blood cells (extramedullary hematopoiesis). As a result, splenomegaly and hepatomegaly develop and cause symptoms.^1,6 Splenomegaly develops in approximately 90% of patients with MF.^1,7

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Role of Inflammation

Approximately 50% to 60% of patients with MF have JAK2 mutations, particularly the JAK2 V617F mutation,⁸ which activates 3 myeloid cytokine receptors: the erythropoietin receptor, the granulocyte colony-stimulating factor receptor, and the myeloproliferative leukemia virus (MPL) receptor.⁴

These receptors enable the activation of erythrocytes, granulocytes/monocytes, and platelets to secrete cytokines, including transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), interleukin 1 (IL-1), epidermal growth factor (EGF), and basic fibroblast growth factor. The cytokines promote fibroblast proliferation and hyperactivity, as well as endothelial proliferation and neo-angiogenesis in the bone marrow.⁹ 

Osteoprotegerin, IL-6, bone morphogenetic protein 2 (BMP-2), and RANTES (regulated upon activation, normal T cell expressed and presumably secreted) also contribute to the proinflammatory, angiogenic, and profibrotic milieu.¹⁰ It is believed that all these proinflammatory cytokines heavily mediate bone marrow fibrosis and contribute to MF progression.¹¹

Elevated cytokine levels correlate with a poor prognosis. Particular elevation of IL-8/CXCL8 can predict transformation of MF to secondary acute myeloid leukemia. Elevated tumor necrosis factor alpha (TNF-α) may contribute to malignant clonal dominance, favoring the survival of mutant hematopoietic stem cells over normal ones.¹¹

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Metabolic Expansion

An established diagnostic biomarker for MF is lactate dehydrogenase (LDH), an enzyme indicative of leukocyte turnover. Lactate, a metabolite of LDH, is taken up by malignant cells and used for oxidative metabolism, thus promoting endothelial neo-angiogenesis and T-cell inhibition. The cancer cells interact with nearby mesenchymal stromal cells, causing them to become glycolytic and export lactate. The exported lactate is taken up by the cancer cells, driving a continuous metabolic cycle involved in immune system impairment and the promotion of bone marrow fibrosis in MF.¹⁰

Read more about MF histology

References

1. Primary myelofibrosis. Medline Plus. Accessed December 18, 2022.
2. Liesveld J. Myelofibrosis.  MSD Manual Consumer Version. Accessed December 19, 2022.
3. Tefferi A. Pathogenic mechanisms in primary myelofibrosis. UpToDate. Accessed December 16, 2022.
4. Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667-679. doi:10.1182/blood-2016-10-695940
5. Patel KP, Newberry KJ, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126(6):790-797. doi:10.1182/blood-2015-03-633404
6. Lal A. Primary myelofibrosis clinical presentation: history. Medscape. Updated September 21, 2022. Accessed December 18, 2022.
7. Lal A. Primary myelofibrosis clinical presentation: physical examination. Medscape. Updated September 21, 2022. Accessed December 18, 2022.
8. Lal A. Primary myelofibrosis: etiology. Medscape. Updated September 21, 2022. Accessed December 18, 2022.
9. Lal A. Primary myelofibrosis: pathophysiology Medscape. Updated September 21, 2022. Accessed December 16, 2022.
10. Giallongo C, Spampinato M, La Spina E, et al. Lactate as metabolic link between cancer cells and tumor microenvironment in myelofibrosis patients. Blood. 2020;136(Suppl 1):26. doi:10.1182/blood-2020-142007
11. 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

Reviewed by Debjyoti Talukdar, MD, on 12/28/2022.

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Alecia Maringola, SMA Contributor

Alecia Maringola, who waged a lifelong, courageous battle with the rare disease spinal muscular atrophy (SMA), passed away from complications from her disease on December 1, 2022. In her last year of life, Alecia was a patient columnist for Rare Disease Advisor. Week after week, Alecia's columns spoke directly to patients with SMA and their families and health care providers. Raised in Southington, Connecticut, Alecia was diagnosed with SMA at 13 months of age. She was challenged by a disease that progressively weakens voluntary muscles, along with scoliosis. She credited her faith in God and the love of family, calling them “of the utmost importance to me.”