Myelofibrosis

Definition:

Myelofibrosis (MF), one of the three classic Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), is characterized by symptoms mainly derived from anemia and splenomegaly and constitutional symptoms and associated with a median survival around 6 years. Most MPN patients harbor an acquired mutation in the hemopoietic cells, the V617F mutation, located in the pseudokinase domain of the JAK2 gene. This mutation results in a gain of function, i.e., in the constitutive activation of the JAK-STAT pathway, which plays an important role in the proliferation, differentiation, and survival of the hemopoietic cells, as well as in the immune function. Besides, a minority of patients with MF (most of them negative for the JAK2 mutation) harbor other JAK-STAT-activating mutation, the MPL mutation, in the gene of the receptor of the thrombopoietin. Recently, mutations in the CALR gene have been described in 86% of cases with primary MF that are negative for JAK2 or MPL mutations. CALR mutation also showed cytokine independent growth of cells due to activation of STAT5 involved with the JAK-STAT pathway but its exact role in MPN remains to be clarified.

References:

[1]. Francisco Cervantes, et al. Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. [Content Brief]

[2]. Gabriela S Hobbs, et al. Clinical and molecular genetic characterization of myelofibrosis. Curr Opin Hematol. 2015 Mar;22(2):177-83. [Content Brief]

[3]. Nisha R Singh, et al. Genomic diversity in myeloproliferative neoplasms: focus on myelofibrosis. Transl Pediatr. 2015 Apr;4(2):107-15. [Content Brief]

[4]. Stephen T Oh, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010 Aug 12;116(6):988-92. [Content Brief]

[5]. Terra L Lasho, et al. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time. Br J Haematol. 2006 Dec;135(5):683-7. [Content Brief]

[6]. Thorsten Klampfl, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379-90. [Content Brief]

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