Heterogeneous JAK2V617F Allele Burden in Essential Thrombocytosis: Gender and Clinical Correlates.
Authors: Pemmaraju Naveen , Moliterno Alison R. , Williams Donna , Rogers Ophelia , Spivak Jerry L. 
Published: October 2019

Abstract
Essential thrombocytosis (ET) is the most heterogeneous of the chronic myeloproliferative disorders (MPD) when assessed by clonality assays, PRV-1, Mpl expression and JAK2V617F status. The purpose of this study was to prospectively analyze a cohort of 68 ET patients to determine the relationship of quantitative JAK2V617F allele percentage to disease features. The cohort consisted of 18 men and 50 women followed at our institution with a median disease duration of 7 years (range 1–24 years); all patients were clinically assessed between 2005 and 2006. Neutrophil genomic DNA and platelet cDNA were prepared from blood samples obtained at the time of clinical assessment and quantitative JAK2V617F measurements were made using a sensitive allele-specific, quantitative PCR assay. Median patient age at diagnosis was 47 years (range 2–84) without gender difference. JAK2V617F-positive patients were older than patients without the mutation (57 versus 41 years, p=<0.001). When assessed by neutrophil genomic DNA, more male than female ET patients were JAK2V617F-positive (56% versus 36%); however, when assessed by platelet cDNA, males and females had a similar JAK2V617F prevalence (60% versus 73%). JAK2V617F-positive male ET patients also had a higher median neutrophil allele percentage than JAK2V617F-positive female patients (47%, range 17–63, versus 31%, range 5–64). In 25 ET patients (15 female and 10 male), simultaneous JAK2V617F allele assessment in neutrophils and platelets identified 4 patients, all female, who were JAK2V617F-positive only in their platelet cDNA. JAK2V617F status did not correlate with the prevalence of erythromelalgia (4/11 JAK2V617F-positive), transient ischemic attack (3/7 JAK2V617F-positive), stroke (1/4 JAK2V617F-positive), migraine (7/18 JAK2V617F-positive), acute coronary syndromes (2/6 JAKV617F-positive), deep venous thrombosis (0/1 JAK2V617F-positive), peripheral arterial thrombosis (1/2 JAKV617F-positive), or hydroxyurea, interferon or anagrelide use. When controlled for gender, there were no significant differences in leukocyte count, hemoglobin concentration, reticulocyte count or platelet count between JAK2V617F-positive and -negative individuals. JAK2V617F status did not correlate with a family history of an MPD, present in 6 JAK2V617F-negative patients (3 male, 3 female) and 9 JAK2V617F-positive patients (2 male, 7 female). During the study period, phenotypic conversion occurred in 5 patients with a median disease duration of 10 years (range 3–20 years); 3 converted to polycythemia vera (2/3 JAK2V617F positive) and 2 to idiopathic myelofibrosis (both JAK2V617F-positive). In those patients with phenotypic conversion (3 men and 2 women), the JAK2V617F allele percentages either increased to or were at the upper end of the cohort JAK2V617F allele percentage distribution. In summary, in a well-defined, prospectively studied ET patient population, the neutrophil JAK2V617F allele burden was higher in men than women and in some women, JAK2V617F expression was restricted to platelets alone. While phenotypic conversion was associated with an increasing or high JAK2V617F allele percentage, neutrophil JAK2V617F did not correlate with platelet-mediated micro- or macrovascular events nor was there any correlation with hemoglobin, white cell count or platelet count. We conclude that JAK2V617F allele burden in ET is gender-specific and that comparison of JAK2V617F-positive and -negative ET patients must consider both neutrophil and platelet quantitative JAK2V617F allele expression.