JAK2^V617F and ischemic stroke: CHIP or CMD-NBV?

TO THE EDITOR:

Kristiansen et al studied 538 people with recent ischemic stroke, 61 of whom had JAK2^V617F. They reported this frequency was 2.4 times greater than that of matched controls without ischemic cerebral disease.¹ Based on these data, the authors argued that JAK2^V617F is a new cerebrovascular disease risk factor.

The association of the somatic JAK2^V617F mutation with arterial thrombosis should consider several disorders also associated with thrombotic risk and JAK2^V617F. Nine of 61 subjects of the Kristiansen cohort had a BCR::ABL–negative myeloproliferative neoplasm (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The remaining 52 were classified as having JAK2 mutation–associated clonal hematopoiesis of indeterminate potential (CHIP).

Including JAK2^V617F in CHIP fits the diagnostic criteria provided by Steensma et al and the seminal series in which JAK2^V617F occurred along with mutations in DNMT, TET2, and ASXL1.^2-4 It should be noted that the original CHIP definition included a variant allele frequency (VAF) > 2%. However, 46 of 61 subjects in the study by Kristiansen et al had a VAF < 1%. This VAF threshold has been lowered to 0.02%, fitting the level of detection of whole exome sequencing.⁵ 

JAK2^V617F-associated CHIP has several distinctive features, including higher frequencies of splanchnic vein thrombosis and cardiovascular disease than CHIP, associated with other somatic mutations.^3,6 JAK2^V617F encodes a constitutively activated tyrosine kinase in the STAT signaling pathway, a regulator of myeloproliferation and inflammation. This differs from other CHIP-associated mutations, and including JAK2^V617F in the definition of CHIP is controversial. For example, Cassinat et al argued JAK2^V617F in CHIP is misleading because this is de facto proof of having an MPN.⁷ JAK2^V617F in otherwise healthy individuals often causes deregulated red blood cell and platelet production.

In the study of Kristiansen et al, 25 participants with JAK2^V617F but no MPN diagnosis had hemoglobin, white blood cell, or platelet concentration above normal.¹ More compelling is the argument that persons with normal blood cell concentrations but with JAK2^V617F, even at very low VAF, often have abnormal bone marrow histology, even when it is not diagnostic of an MPN.⁸ Carrà et al reported participants whom they described as having JAK2^V617F-associated CHIP showing increased bone marrow cellularity, an increased erythroid component, and occasional hyperplasia of megakaryocytes with dysplasia.⁶ 

There are many descriptions of people with JAK2^V617F and so called latent MPN with an increased risk of thrombotic events. We recently proposed that these people have an MPN subtype characterized by normal or minimally elevated blood cell concentrations, no signs of disease activity, and a bone marrow with megakaryocyte hyperplasia and dysplasia, which we termed as clonal megakaryocyte dysplasia with normal blood values (CMD-NBV).⁹ In 15 cases of CMD-NBV we studied, 3 had an otherwise unexplained arterial thrombosis, including stroke, and 10 had JAK2^V617F, with 3 having a VAF < 1%.

We suggest that for people with JAK2^V617F-associated CHIP, a diagnosis of CMD-NBV should be evaluated by a bone marrow study. People with bone marrow histology with minimal megakaryocyte abnormalities deserve further study and are likely to have CMD-NBV.

In their discussion, Kristiansen et al proposed JAK2^V617F mutation as a new biomarker for ischemic stroke. We suggest that for individuals with ischemic stroke and an apparently JAK2^V617F-associated CHIP, careful study of bone marrow histology can help identify CMD-NBV.

Acknowledgments: This work was supported by Associazione Italiana per la Ricerca sul Cancro 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project #21267 (MYeloid Research Venture Associazione Italiana per la Ricerca sul Cancro); by Ricerca Corrente Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy (project number 874, code number 08054517; V.R.).

Contribution: G.B. wrote the first version of the manuscript, and V.R. and R.P.G. contributed to the final version of the manuscript.

Conflict-of-interest disclosure: R.P.G. is a consultant for BeiGene Ltd, Fusion Pharma LLC, LaJolla NanoMedical Inc, Mingsight Parmaceuticals Inc, Kite Pharma, and CStone Pharmaceuticals; adviser for Antegene Biotech LLC, Medical Director and FFF Enterprises Inc; partner in AZACA Inc; member of the board of directors in RakFond Foundation for Cancer Research Support; and a scientific advisory board member in StemRad Ltd. The remaining authors declare no competing financial interests.

Correspondence: Giovanni Barosi, Biotechnology, Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Viale Golgi 19, 27100 Pavia, Italy; e-mail: barosig@smatteo.pv.it.