The Phenotype of JAK2 Exon 12-Mutated Myeloproliferative Neoplasms

Stephen E. Langabeer1

1 Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland.

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Stephen E. Langabeer, Cancer Molecular Diagnostics, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, D08 W9RT, Ireland.
Email: slangabeer@stjames.ie
Telephone: +353 14162413

Received: June 4, 2021
Revised: July 5, 2021
Accepted: July 7, 2021
Published online: July 12, 2021


While the majority of patients with polycythemia vera (PV) have an acquired JAK2 V617F mutation, a minority (< 5%) harbor alternative JAK2 mutations in exon 12 also predominantly associated with an erythroid phenotype. However, recent reports of JAK2 exon 12 mutations in patients with other myeloproliferative neoplasms suggest that this may not be the case. These findings have potential implications for molecular diagnostic algorithms.

Key words: Polycythemia vera; JAK2 exon 12 mutations; Myeloproliferative neoplasms; Molecular diagnostics

© 2021 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Langabeer SE. The Phenotype of JAK2 Exon 12-Mutated Myeloproliferative Neoplasms. International Journal of Hematology Research 2021; 6(1): 193-194 Available from: URL: http://www.ghrnet.org/index.php/ijhr/article/view/3162


Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis with other features including leucocytosis, thrombocytosis, splenomegaly, thrombosis, bleeding, pruritus and a risk of myelofibrotic or leukemic transformation[1]. At the molecular level, more than 95% of PV patients harbour the JAK2 V617F mutation with less than 5% of patients having evidence of JAK2 exon 12 mutations. JAK2 exon 12 mutations occur within residues 536-547 adjacent to the pseudo-kinase domain-encoding region and comprise of non-synonymous substitutions, deletion/insertions and duplications[2]. Compared to their JAK2 V617F counterparts, PV patients with JAK2 exon 12 mutations tend to be younger, nearly always have a lower serum erythropoietin level, and have a more pronounced bone marrow erythroid hyperplasia. Despite these trends, up to one third of patients present with a thrombocytosis[3-6].

Two recent studies have reported the presence of JAK2 exon 12 mutations in MPN patients with other phenotypes. Firstly, a p.H538_K539delinsL JAK2 exon 12 mutation was reported in a patient with myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis in addition to SF3B1 and TET2 mutations. Sequence analysis of burst-forming units-erythroid colonies implies the acquisition of the dominant SF3B1 mutation prior to the JAK2 exon 12 mutation[7]. Secondly, p.H538_K539delinsQL and p.H538_K539delinsL JAK2 exon 12 mutations were reported in two cases of myelofibrosis. The short clinical histories of both patients argue in favor of a diagnosis of primary myelofibrosis as opposed to post-PV myelofibrosis[8].

Similar to the JAK2 V617F that can occur in several MPN phenotypes, it is apparent that JAK2 exon 12 mutations can occur, albeit very rarely, in types of MPN other than PV. Order of mutation acquisition is known to influence the MPN phenotype though other factors such as the burden of the driver mutation, additional mutations, germline predisposition, the bone marrow microenvironment, cell of origin, and the presence of clonal hematopoiesis are all likely to contribute to the clinical phenotype[9].

The impact the above findings will have on the molecular diagnostic algorithm for MPN remains to be realised as screening for JAK2 exon 12 mutations reflexively follows that of the JAK2 V617F in patients with a persistent erythrocytosis. However, the increasing adoption of next-generation sequencing myeloid gene panels for MPN diagnosis and prognosis may negate this requirement.


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