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

doi:10.4236/ijcm.2013.412A1003

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International Journal of Clinical Medicine, 2013, 4, 10-15

Published Online December 2013 (http://www.scirp.org/journal/ijcm)

http://dx.doi.org/10.4236/ijcm.2013.412A1003

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: *[email protected]

Received October 19th, 2013; revised November 20th, 2013; accepted December 12th, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accor-

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 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 %

[14].

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

thought.

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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