Myelofibrosis Pathophysiology

Myelofibrosis Is Characterized by Bone Marrow and Blood Cell Abnormalities

Myelofibrosis is a progressive hematopoietic stem cell disorder1,2 characterized by bone marrow3-5 and blood cell abnormalities.4

Both marrow fibrosis and insufficient hematopoiesis drive extramedullary hematopoiesis, particularly in the spleen.6 Blood cell abnormalities in myelofibrosis include a reduction in the number of red blood cells and a variable or increased white blood cell count.4

Myelofibrosis is a complex disease characterized by multiple genetic, epigenetic, and cellular alterations. The primary driver of myelofibrosis, however, is overactive JAK signaling, including overactivation of both normal (wild-type) and mutated JAK1 and JAK2 expression.7

No Single Hallmark Mutation Has Been Identified for Myelofibrosis

Although numerous JAK pathway mutations have been identified in patients with myelofibrosis, no single hallmark mutation has been identified for the disease.8-10 Approximately 50% to 60% of affected patients have a mutation of the JAK2 gene.10 Several other mutations have been observed, including the CALR mutation which is found in approximately 25% of patients with myelofibrosis.11

Patients with myelofibrosis also have high levels of circulating inflammatory cytokines, such as interleukin-6, which likely contribute to a hypermetabolic state and cytokine-mediated systemic symptoms.12

Examining Bone Marrow
image of normal bone marrow vs bone marrow presenting with myelofibrosis disease
References

1. Campbell PJ, Green AR. N Engl J Med. 2006;355:2452-2466. 2. Rambaldi A, Barbui T, Barosi G. Hematology Am Soc Hematol Educ Program. 2008;2008:83-91. 3. Vannucchi AM, Guglielmelli P, Tefferi A. CA Cancer J Clin. 2009;59:171-191. 4. Data on file. Incyte Corporation. 5. Abdel-Wahab O, Manshouri T, Patel J, et al. Cancer Res. 2010;70:447-452. 6. Holden C, Hennessy O, Lee WK. AJR Am J Roentgenol. 2006;186:507-510. 7. Verstovsek S. Hematology Am Soc Hematol Educ Program. 2009:636-642. 8. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Nat Rev Cancer. 2007;7:673-683. 9. Verstovsek S, Kiladjian J-J, Sandor VA, et al. Poster presented at the 48th annual meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. 10. Cross NC. Hematology Am Soc Hematol Educ Program. 2011;2011:208-214. 11. Rumi E, Pietra D, Pascutto C, et al. Blood. 2014;124(7):1062-1069. 12. Verstovsek S. Clin Cancer Res. 2010;16:1988-1996. 13. Arber DA, Orazi A, Hasserjian R, et al. Blood. 2016;127(20):2391-2405.

 
Resources
By: World Health Organization (WHO)
A diagnostic worksheet from the WHO for primary MF, PV, and ET.
By: International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
Diagnostic criteria from the IWG-MRT.