The following case study focuses on a 59-year-old man who was well
until approximately six months ago when he developed increasing
abdominal discomfort, early satiety, and weight loss of 15 pounds due
to poor appetite. Test your knowledge by reading the background
information below and making the proper selection.
The patient’s white blood cell count was 1.8 x 103 cells/mm3 with an absolute neutrophil count of 1.3 x 103 cells/mm3, hemoglobin 9.2 gm/dl, and a platelet count of 77,000 cells/mm3.
A bone marrow biopsy resulted in a "dry" aspirate, but the core biopsy
was markedly fibrotic (MF-3 according to the European consensus grading
system).1 An estimate of the blast count based upon touch preps as well as a CD34+/CD117+
immunostain of the core biopsy demonstrated only 1.2 percent blasts.
Qualitative molecular testing demonstrated the JAK2-V617F mutation.
Which of the following statements is most accurate?
- The presence of the JAK2-V617F mutation establishes the diagnosis of a myeloproliferative disorder.
- The absence of the JAK2-V617F mutation rules out the diagnosis of primary polycythemia.
mutant allele frequency testing indicates that a higher proportion of
the JAK2-V617F alleles are identified in patients with primary
polycythemia vera (PV)
compared with patients with essential thrombocythemia (ET).
of patients with myelofibrosis with JAK2 inhibitors can improve
symptoms, reduce spleen size, and eliminate the presence of the
- Quantitative mutant allele frequency testing
indicates that a higher proportion of the JAK2-V617F alleles are
identified in patients with primary polycythemia vera (PV)
compared with patients with essential thrombocythemia (ET).
The discovery of the Philadelphia chromosome resulting from the translocation of the Abl gene on chromosome 9 to chromosome 22 adjacent to the Bcr
gene and the subsequent development of molecularly targeted therapies
with tyrosine kinase inhibitors (TKI) have revolutionized the treatment
of chronic myeloid leukemia (CML). Subsequently, characterization of
the somatic mutation in the JAK2 gene, which results in a
valine to phenylalanine substitution at position 617 (JAK2-V617F) in a
significant number of patients with Bcr-Abl negative
myeloproliferative diseases (MPDs) has initiated a search for effective
targeted therapies for these conditions as well.2-4
Unlike the Bcr-Abl transgene’s association with CML, the
absence of the JAK2-V617F mutation does not rule out the presence of
primary PV, ET, or primary myelofibrosis (PMF). Moreover, its presence
does not establish the diagnosis of any of the MPDs. This somatic
alteration can also be found infrequently in atypical CML, chronic
myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL),
hypereosinophilic syndrome (HES), and myelodysplastic syndrome (MDS).5,6
Gene dosage plays a role in a number of human diseases including the
amplification of the her-2/neu kinase in breast cancer and c-met
amplification in colon and lung cancers. However, the phenomenon that
the degree of expression of a single gene alteration can modulate the
phenotype of a disease is relatively unique to JAK2. Recently,
investigators demonstrated that the ratio of mutant to normal JAK2
alleles was higher in patients with PV and PMF compared with patients
with ET.7 This led to the possibility that the allele
frequency, and thus gene dosage, may alter the phenotype of the
disease. Through the utilization of a Cre-recombinase system that
allowed for varied expression of the human V617F mutant JAK2 allele in
mice, researchers demonstrated that mice expressing higher levels of
the mutant JAK2 displayed a phenotype more consistent with PV, while
mice harboring lower levels of expression of the mutant JAK2 allele had
an ET phenotype.
Because of the purported role that the Janus kinase plays in the development of the JAK2+
MPDs, researchers have begun to develop and test a number of JAK2
inhibitors in these disorders. CEP701 is a small molecule Flt-3
inhibitor that has completed phase I/II testing in AML, but it is also
capable of binding the ATP-binding site on JAK2. In vitro,
CEP701 leads to reduced proliferative capacity of erythroid progenitor
cells from patients with MPDs, but the suppression is independent of
the JAK2 phenotype.8 Verstovsek and colleagues recently
presented their phase I/II experience with INCB18242 in patients with
PMF or post-PV/ET myelofibrosis at the ASCO annual meeting.9
Patients treated with INCB18242 had a marked reduction in splenomegaly
as well as a modest, but statistically significant, reduction in the
JAK2-V617F allele burden. Interestingly, a reduction in the
proinflammatory cytokine IL-6 was also noted, perhaps contributing to
the reduction in constitutional symptoms. Recently, researchers began
phase I testing of TG101348, a relatively selective JAK2 inhibitor, in
patients with PMF, but the data on its clinical activity are too
immature to report.
The field of MPDs was permanently altered with the development of
the molecularly targeted TKIs for CML. With the recent advent of
molecular testing and the identification of the JAK2-V617F mutation, we
are hopefully beginning to unravel the mysteries of some of the
remaining MPDs. As with CML, molecularly targeted treatments are
emerging for these conditions, but they are still very early in their
- Thiele J, Kvasnicka HM, Facchetti F, et al. European
consensus on grading bone marrow fibrosis and assessment of
cellularity. Haematologica. 2005;90:1128-32.
C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading
to constitutive signalling causes polycythaemia vera. Nature.
- Levine RL, Wadleigh M,
Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in
polycythemia vera, essential thrombocythemia, and myeloid metaplasia
with myelofibrosis. Cancer Cell. 2005;7:387-97.
EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine
kinase JAK2 in human myeloproliferative disorders. Lancet.
- Ingram W, Lea NC, Cervera
J, et al. The JAK2 V617F mutation identifies a subgroup of MDS patients
with isolated deletion 5q and a proliferative bone marrow. Leukemia.
- Steensma DP, Dewald GW, Lasho TL, et al. The
JAK2 V617F activating tyrosine kinase mutation is an infrequent event
in both “atypical” myeloproliferative disorders and myelodysplastic
syndromes. Blood. 2005;106:1207-9.
- Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111:3931-40..
- Hexner EO, Serdikoff C, Jan M, et al. Lestaurtinib
(CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and
the proliferation of primary erythroid cells from patients with
myeloproliferative disorders. Blood. 2008;111:5663-71.
S, Kantarjian HM, Pardanani A, et al. A phase I/II study of INCB018424,
an oral, selective JAK inhibitor, in patients with primary
myelofibrosis (PMF) and post polycythemia vera/essential
thrombocythemia myelofibrosis (Post-PV/ET MF). J Clin Oncol.
Case study submitted by Dale Bixby, MD, PhD, of the University of Michigan.
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