The JAK2<sup>V617F</sup> Mutation Seen in Myeloproliferative Neoplasms (MPNs) Occurs in Patients with Inflammatory Bowel Disease: Implications of a Pilot Study

Abstract

Patients with IBD frequently have hematologic abnormalities suggestive of JAK2 mutated MPNs, but are traditionally classified as reactive processes. Haplotype 46/1 is a well-characterized genetic predisposition, common to both inflammatory bowel disease (IBD) and myeloproliferative neoplasms (MPN). In view of this shared genetic predisposition, we measured the frequency of the JAK2 V617F mutation in IBD patients with thrombocytosis or erythrocytosis, in order to ascertain whether a higher than expected proportion of these patients may in fact have underlying MPNs. 1121 patients were identified with an active diagnosis of Crohn's disease or ulcerative colitis, of which 474 had either thrombocytosis or erythrocytosis. Patients with abnormal counts were tested for the JAK2 V617F mutation during routine follow-up visits. Interim analysis of first 23 patients tested was performed to assess whether the JAK2 V617F positivity rate was statistically significant compared with known expected frequencies in a comparable control population. Of 23 patients, 13 patients had thrombocytosis and 10 had erythrocytosis. Three patients with thrombocytosis (23%), and 1 patient with erythrocytosis (10%), tested positive for JAK2 V617F , exceeding the expected thresholds for statistical significance. In patients with IBD and thrombocytosis or erythrocytosis, a meaningful proportion may harbor an undiagnosed MPN, as indicated by clonal abnormalities such as JAK2 V617F. These findings imply the need for increased testing of these patients for clonal hematologic abnormalities, and importantly, if found, suggest the need for therapeutic strategies with drugs, such as JAK2 inhibitors, in patients with both MPN and IBD.

Impact of Host, Lifestyle and Environmental Factors in the Pathogenesis of MPN

“…Autoimmune disease, most notably inflammatory bowel disease, has been associated with an increased risk of clonal hematopoiesis. Analysis of patients with thrombocytosis in an inflammatory bowel clinic revealed that 23% of them harbored JAK2 V617F mutations [30], this highlights that some cases of assumed reactive thrombocytosis in a patient with an inflammatory disease may actually be MPN. Also, a cohort of patients with ulcerative colitis was found to have an increased rate of CHIP, in particular with DNMT3A and PPM1D mutations [17].…”

Risk of Inflammatory Bowel Disease in Patients with Chronic Myeloproliferative Neoplasms: A Danish Nationwide Cohort Study

“…However, the results are inconclusive, and recently published data again show diverging results of the risk for hematological malignancies in patients with IBD [13,14]. Of note, the specific relationship with MPNs has been sparsely investigated in patients with IBD, since MPNs have not been included as myeloid malignancies in all previous studies [12,14,15]. Nevertheless, Cheddani and colleagues found that the risk of myeloid malignancies (chronic myeloid leukemia, acute myeloid leukemia, ET, PV, and MF), was increased 2-fold among 844 elderly patients with IBD from France compared to that observed in a population-based cancer registry [14].…”

“…For instance, as the specific JAK2 rs10758669 single nucleotide polymorphism, part of the haplotype 46/1, is shown to be associated with both CD and UC [ 27 , 28 , 30 ]. Strengthening the notion of shared genetic predisposition, Kuriakose and colleagues showed that the JAK2 V617F mutation was present in four of 23 patients with IBD who also had increased erythrocyte or platelet counts [ 15 ]. Further, in patients with MPN, a correlation between JAK2 V617F positivity and prior autoimmune disease has been observed [ 36 ].…”

“…Studies show that patients with IBD are at increased risk of various chronic conditions, such as cardio-vascular diseases, osteoporotic fractures, and other immune-mediated diseases [3][4][5][6][7]. In addition, the risk of gastrointestinal cancers is increased, as is the risk of some extra-intestinal malignancies, including hematological cancers [8][9][10][11][12][13][14][15]. Conversely, the subsequent risk of IBD in patients with hematological cancers has not been studied.…”

The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies

“…It has been proposed that the JAK2 46/1 haplotype results in an augmented response to cytokine stimulation, leading to increased inflammation [ 21 ]. Interestingly, a study found JAK2 V617F in about 20% of people with mild thrombocytosis in an inflammatory bowel disease (IBD) clinic, suggesting that a significant fraction of people with IBD harbor a JAK2 V617F clone [ 22 ]. In addition, MPN patients have a >2-fold increased risk of IBD, a result that links these two disease entities with potentially common predispositions.…”