International Journal of Clinical Medicine, 2013, 4, 10-15
Published Online December 2013 (
Open Access IJCM
The JAK2V617F Mutation Seen in Myeloproliferative
Neoplasms (MPNs) Occurs in Patients with Inflammatory
Bowel Disease: Implications of a Pilot Study
Emil Kuriakose1, Elena Lascu1, Y. Lynn Wang2, Stefani Gjoni1, Nicholas C. P. Cross3,
Ruth Baumann1, Kerilee Tam4, Ellen Scherl4, Randy S. Longman4, Richard T. Silver1*
1Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, USA; 2Department of Pathology, Uni-
versity of Chicago, Chicago, USA; 3Wessex Regional Genetics Laboratory, Salisbury District Hospital, University of Southampton,
Salisbury, UK; 4Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology, Weill Cornell Medical College,
New York, USA.
Email: *
Received October 19th, 2013; revised November 20th, 2013; accepted December 12th, 2013
Copyright © 2013 Emil Kuriakose et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-
dance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intellectual
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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 pred isposition, common to bo th inflam-
matory bowel disease (IBD) and myeloproliferative neoplasms (MPN). In view of this shared genetic predisposition, we
measured the frequency of the JAK2V617F 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 activ e diagnosis of Crohn’s disease or ulcerative colitis, of wh ich 474 had eith er thromboc ytosis
or erythrocytosis. Patients with abnormal counts were tested for the JAK2V617F mutation during routin e follow-up visits.
Interim analysis of first 23 patients tested was performed to assess whether the JAK2V617F positivity rate was statisti-
cally 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 JAK2V617F, 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 JAK2V617F. These findings imply the need for increased testing of these pa-
tients 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.
Keywords: JAK2V617F; Myeloproliferative Neoplasms; Inflammatory Bowel Disease; Thrombocythemia; Polycythemia
1. Introduction
Thrombocytosis is a common finding in patients with
inflammatory bowel disease (IBD), as well as other au-
toimmune diseases and connective tissue disorders [1-3].
Traditionally defined as reactive or secondary thrombo-
cytosis, the increased platelet count in these settings is
attributed to various causes, including chronic inflamma-
tion, bleeding, iron deficiency, and abnormally elevated
serum inflammatory cytokines (e.g. IL6) and growth
factors such as thrombopoietin [3-5]. In contrast, clonal
thrombocytosis as seen in the myeloproliferative neo-
plasms (MPN), including essential thrombocythemia (ET),
polycythemia vera (PV), and primary myelofibrosis
(PMF), carries a significantly higher risk of thromboem-
bolic disease and evolution of the underlying MPN to
acute leukemia, making it important, and challenging, to
clinically distinguish between these two categories in
patients with t hr ombocytosis [3,5].
Clonal thrombocytosis and erythrocytosis are charac-
terized by identifiable cytogenetic or molecular abnor-
*Corresponding a uthor.
The JAK2V617F Mutation Seen in Myeloproliferative Neoplasms (MPNs) Occurs
in Patients with Inflammatory Bowel Disease: Implications of a Pilot Study 11
malities in the hematopoietic stem cells, progenitor cells,
and/or circulating mature leukocytes [5,6]. In the MPNs,
the most common such abnormality is the JAK2V617F
mutation, seen in more than 95% of patients with PV,
and 50% of patients with ET and PMF [7,8]. Since sec-
ondary thrombocytosis occurs more commonly than the
clonal thrombocytosis of the MPNs [4,5], patients with
thrombocytosis in the setting of IBD are commonly and
appropriately diagnosed as having reactive thrombocyto-
sis. However, an important and therapeutically relevant
question that remains unanswered is whether or not a
significant proportion of these patients might have un-
recognized clonal thrombocytosis.
Large population-based studies have shown that pa-
tients with autoimmune diseases including IBD are more
predisposed to developing MPNs [8]. Patients with a
history of Crohn’s disease (CD) and other autoimmune
disorders are 2 to 3 times more likely to develop MPN
compared to normal controls, translating into a 20% in-
creased lifetime risk [9,10]. Several independently con-
ducted genome-wide association studies (GWAS) in pa-
tients with IBD and MPNs have revealed shared genetic
predisposition factors between these two seemingly dis-
parate diseases [11-15]. GWAS studies in patients with
CD identified predisposition variants in the genes coding
for IL23R, IL12B, JAK2, and STAT3 [11,12]. That
JAK2 and STAT3 are downstream components of IL23
signaling by TH1 and TH17 cells involved in the patho-
genesis of IBD, serves as a possible mechanistic link
among these associations [16].
Intriguingly, the same haplotype 46/1 within the JAK2
gene predisposes to IBD and substantially increases the
risk of acquiring the JAK2V617F mutation and MPNs [13-
15]. The 46/1 haplotype occurs with a frequency as high
as 56% in patients with JAK2 mutated MPNs, compared
with 24% in the general population [13]. Importantly,
this haplotype confers an increased predisposition not
only to acquiring the JAK2V617F mutation, but also to
mutations in JAK2 exon 12, MPL, and JAK2 non-mu-
tated MPNs [13].
Although the mechanisms underlying these shared
predispositions are poorly understood, these findings
collectively suggest a plausible and largely unexplored
pathophysiologic link between IBD and MPNs that may
have important diagnostic and therapeutic implications
for both d iseases.
To examine such a potential link , we performed a pilot
study where patients with IBD and thrombocytosis or
erythrocytosis were screened for the JAK2V617F mutation.
We found that a higher than expected proportion of pa-
tients with IBD has JAK2 mutated clonal rather than
secondary hematologic abnormalities, indicating a here-
tofore unrecognized subset of patients with IBD who
carry the JAK2 mutation. In addition to providing clini-
cal confirmation of a known genetic association between
two seemingly distinct diseases, our findings may lend
credence to the notion of using JAK2 inhibitors to treat
not only MPNs, but also IBD.
2. Patients and Methods
First, after obtaining approval by the Institution al Rev iew
Board (IRB) at Weill Cornell Medical College, we iden-
tified all patients actively being followed at the Center
for Inflammatory Bowel Disease using diagnosis codes
for Crohn’s disease (CD) or ulcerative colitis (UC) in the
electronic medical record (EMR) system. Patients with
IBD and thrombocytosis or erythrocytosis were then
identified by setting appropriate search filters within the
EMR. Thrombocytosis was divided into 3 categories:
patients with platelet counts of 450 to 600 (×103/µL), 600
to 1000 (×103/µL), and greater than 1000 (×103/µL).
Erythrocytosis was similarly categorized into patients
with hemoglobin (Hb) of 16 to 18 g/dL, and more than
18 g/dL. In order to be included in the screen, patients
required elevated platelet or hemoglobin values in the
defined category on at least two separate occasions, no
less than 8 weeks apart. Care was taken to ensure that
none of the patients were receiving medications known
to increase Hb or platelet counts. JAK2V617F mutation
testing on peripheral blood was performed when patients
identified in the screen came for routine follow-up visits
to the IBD Center at Weill Cornell. Informed consent for
JAK2V617F mutational testing was obtained prior to col-
lecting peripheral blood. JAK2V617F allele burdens were
determined by pyrosequencing, which quantifies mutant
alleles more than 5% [14]. If negative by pyrosequencing,
we used an ARMS-PCR assay with a sensitivity of 0.1 %
Interim analysis of the first 23 patients tested for
JAK2V617F (13 with thrombocytosis, 10 with erythrocyto-
sis) was performed as a pilot study, with the intent of
expanding testing to a larger patient cohort only if the
number of positive results met thresholds for statistical
significance, derived using JAK2V617F mutation frequen-
cies in a comparable control population. Given that ET
accounts for approximately 10% of all patients with
thrombocytosis [3,5], of which only half carry the
JAK2V617F mutation [8], a 5% positivity rate would be
predicted in a control population. Based on our sample
size of 13 patients with thrombocytosis, 1 positive result
or an 8% positivity rate was set as the threshold to meet
statistical significance (p < 0.05) using the one-tailed
Chi2 test for categorical variables. Since JAK2 mutated
PV accounts for an even lower proportion of all-comers
with erythrocytosis (<5%) [17], the same threshold level
for statistical significance was set for the 10 patients in
Open Access IJCM
The JAK2V617F Mutation Seen in Myeloproliferative Neoplasms (MPNs) Occurs
in Patients with Inflammatory Bowel Disease: Implications of a Pilot Study
Open Access IJCM
our study who had eryt h rocy tosis. dian age of this group was 36 years (range: 18 - 69 years)
(Table 1). The median platelet count in the thrombocy-
tosis group was 941 × 103/µL (range: 478 - 1677 ×
103/µL); median Hb in the erythrocytosis group was 16.9
g/dL (range: 15.8 - 21.2 g/dL). Other patient characteris-
tics are outlined in Table 1.
3. Results
A screen of the EMR at Weill Cornell Medical College
identified 1121 patients with an active diagnosis of CD
or UC. The median age of this cohort was 39 years (ran-
ge: 18 - 103 years). Of these, 345 (30.7%) had thrombo-
cytosis (platelet count > 450 × 103/µL) and 129 (11.5%)
had erythrocytosis (Hb > 16 g/dL) (Figure 1). Of pa-
tients with thrombocytosis, 60.5% had platelet counts
between 450 - 600 (×103/µL) and the remainder had
counts more than 600 × 103/µL, with 10 patients having
platelet counts more than 1000 × 103/µL (Figure 1).
The median duration of IBD in the 23 patients was 10
years (range: 3 - 52 years). Disease activity, as defined
by the Crohn’s Disease Activity Index (CDAI), was low
in 11, moderate in 5, and severe in 7 patients at the time
of JAK2 mutation testing. All patients had received an
average of at least 4 treatments (range 1 - 12) during their
disease course, including systemic steroids, bowel spe-
cific anti-inflammatory drugs (mesalamine), cytotoxic
drugs (6-MP, methotrexate), and monoclonal antibod-
ies(infliximab, adalimumab, ustekinumab).
Of the 474 patients with abnormal counts, we were
able to test 23 (13 with thrombocytosis and 10 with eryt-
hrocytosis) for JAK2V617F over a period of 6 months. Me-
Figure 1. Results of the EMR screen.
Table 1. Patient demographics.
Variable Number (%)
Median age (yr) 36 (rang: 18 - 69)
Male 16 (70%)
Female 7 (30%)
Crohn’s disease 15 (65%)
Ulcerative colitis 8 (35%)
Erythrocytosis (Hb > 16) 10 (43.5%)
Median (range) 16.9 (15.8 - 21.2)
Thrombocytosis (Plts > 600) 13 (56.5%)
Median (range) 941 (478 - 1677)
Number of patoe n ts found to have MPN 5 (21.7%)
JAK2V617F positive* 4 (17.4%)
JAK2V617F negative** 1 (4%)
*3 with thrombocytosis (ET). 1 with erythrocytosis (undiagnosed MPN); **PMF with thrombocytosis.
The JAK2V617F Mutation Seen in Myeloproliferative Neoplasms (MPNs) Occurs
in Patients with Inflammatory Bowel Disease: Implications of a Pilot Study 13
Three patients in th e thrombocytosis group (23%), and
one patient in the erythrocytosis g roup (10%) tested posi-
tive for the JAK2V617F mutation, exceeding our threshold
positivity level for statistical significance based on the
one-tailed Chi2 test for categorical variables (p < 0.05).
The platelet counts of the 3 thrombocythemic patients
with the JAK2 mutation were 748, 1492, and 734
(×103/µL). All 3 had essential thrombocytosis (ET) and
were on antiplatelet therapy with ASA. One was on sys-
temic anticoagulation for deep vein thrombosis (DVT).
One patient with thrombocytosis who tested negative for
JAK2V617F, had a diagnosis of primary myelofibrosis
(PMF). The patient with erythrocytosis who tested posi-
tive for JAK2V617F had a Hb of 16.7 g/dL and had no
prior history of phlebotomy or known diagnosis of MPN.
4. Discussion
In light of substantial data from GWAS, studies support-
ing a shared genetic predisposition for both MPN and
IBD in the form of the 46/1 haplotype, JAK2V617F testing
in IBD patients would be a step towards validation of
these findings, particularly in patients with hematologic
abnormalities suggestive of MPNs. Our results indicate
that clonal hematologic abnormalities may occur at a
greater frequency in this patient cohort than traditionally
Of our 13 patients with thrombocytosis, 23% had the
JAK2V617F mutation, significantly exceeding the expected
frequency of clonal causes in all-comers with thrombo-
cytosis. Since only 50% of patients with ET and PMF
carry the JAK2 mutation [7,8], the actual proportion of
IBD patients with clonal thrombocytosis may potentially
be twice that observed in this study, since we only
screened for those carrying the mutation. Indeed, our
pilot study revealed one patient with JAK2 wild-type
PMF. As testing is expanded to the larger cohort of pa-
tients, identifying tho se patients with JAK2 wild-type ET
or PMF will entail further diagnostic tests for MPNs as
recently outlined [18,19]. Our findings imply that a non-
trivial proportion (at least 20%) of patients with IBD and
thrombocytosis may have an underlying MPN. Whether
or not this is true within the entire spectrum of autoim-
mune diseases with thrombocytosis is unknown, and
warrants further study.
As with thrombocytosis, erythrocytosis occurs more
commonly from secondary causes than clonal JAK2 mu-
tated PV [17]. Most patients with IBD have low Hb ow-
ing to anemia of chronic disease and/or iron deficiency
anemia [20], but experience significant fluctuations in
Hb over time from episodic volume depletion and he-
moconcentration or blood transfusions. Taken together,
one would predict a low likelihood of identifying true
clonal erythrocytosis in IBD patients using only Hb as a
screening tool. Therefore, the finding of JAK2V617F in
even 1 of our 10 patients is especially striking. As 10%
in our entire cohort of more than a thousand IBD patients
had erythrocytosis, the exp ansion phase of the study may
approximate the actual incidence of clonal erythrocytosis
(PV) in these patients.
Patients with IBD are at the increased risk of both ar-
terial and venous thrombosis, as high as a 40% frequency
of thromboembolic disease [2-5], and at a 3.6 fold in-
creased risk of thrombosis compared with normals [3].
Since thromboembolic disease is one of the most fre-
quently observed manifestations of MPNs, particularly in
those carrying JAK2 mutations [5,21], coexisting IBD
and MPN would arguably increase the baseline risk of
thrombosis by several fold in these patients. A small
study in which 48 patients with IBD and thrombotic
events were tested for the JAK2V617F mutation was nega-
tive, although none of the patients had overt hematologic
abnormalities [22]. Since only a small minority of pa-
tients with JAK2 mutated MPNs have normal peripheral
counts by definition [19], testing for JAK2 mutations in
IBD patients with hematologic abnormalities has a higher
likelihood of identifying those at the increased risk of
thrombosis. Indeed, in our pilo t study of selected patien ts
with hematologic abnormalities, one of 13 patients with
thrombocytosis had a thrombotic event in the setting of
IBD and JAK2 mutation. That 46/1 is one among several
haplotypes within various genes involved in the IL23 and
JAK2 signaling pathway, suggests increased JAK2 sig-
naling in IBD, even in the absence of somatically ac-
quired mutations [16]. Since it is known that 46/1 in-
creases the chance of acquiring the JAK2V617F and other
mutations in the JAK2 gene, the importan t question aris-
es from whether JAK2 mutations may contribute to the
pathophysiology of IBD, independent of any effect on
the hematopoietic compartment.
Since several JAK2 inhibitors are now available and
show efficacy in treating both JAK2 mutated and
non-mutated MPNs [23,24], the finding of a higher than
expected JAK2 mutation rate in IBDs poses the thera-
peutic question about whether these drugs might improve
symptoms of IBD in refractory patients. This question
has been explored with the JAK1 and JAK3 inhibitor
tofacitinib in ulcerative colitis [25], but JAK2 specific
inhibitors have yet to undergo large-scale testing in this
disease setting. Our findings support a common link be-
tween MPNs and IBDs warrant therapeutic trials of
JAK2 inhibitors in IBD patients, whether hematologic
abnormalities are present or not.
In conclusion, the results of this pilot study indicate
that the actual incidence of clonal thrombocytosis or
erythrocytosis in patients with IBD may be more sub-
stantial than traditionally thought. Our findings may rep-
Open Access IJCM
The JAK2V617F Mutation Seen in Myeloproliferative Neoplasms (MPNs) Occurs
in Patients with Inflammatory Bowel Disease: Implications of a Pilot Study
resent the clinical manifestation of a shared genetic pre-
disposition for IBD and MPN in the form of the 46/1
haplotype, and therefore, warrant not only large scale
testing for MPNs in patients with IBD, but therapeutic
trials of drugs with potential to simultaneously improve
outcomes for both diseases.
5. Acknowledgements
1) E. T. K. was supported by the Johns Family Fel-
lowship in Myeloproliferative Neoplasms, The Cancer
Research and Treatment Fun d, I nc., Ne w Y or k, NY.
2) We are grateful to Jacob Weiser for conducting the
EMR screen to identify the patients for this study.
3) This work was supported in p art by th e William and
Judy Higgins Trust of the Cancer Research and Treat-
ment Fund, I n c., New York, NY.
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in Patients with Inflammatory Bowel Disease: Implications of a Pilot Study
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