Division of Hematology, Mayo Clinic, Rochester, MN, United States
Correspondence: Ayalew Tefferi, MD
Mayo Clinic
200 First Street SW
Rochester MN 55905
Tel: +1 507 284 2479
Fax: +1 507 266 4972
tefferi.ayalew@mayo.edu
September 2008
Typically, JAK kinases function through their interaction with cytokine receptors
that lack intrinsic kinase activity. Ligand binding (e.g. erythropoietin, thrombopoietin)
to the appropriate cytokine receptor (type 1 or type 2 cytokine receptors; e.g.
EpoR, MPL) results in juxtaposition of JAKs followed by JAK kinase phosphorylation
and activation, cytokine receptor phosphorylation and creates a docking site
for the recruitment and activation of signal transducers and activators of transcription
(STATs) (Mertens and Darnell, 2007). Following phosphorylation, activated STATs
dimerize and translocate into the nucleus to induce target gene transcription.
This entire process is tightly regulated at multiple levels by protein tyrosine
phosphatases, suppressors of cytokine signaling (SOCS) and protein inhibitors
of activated STAT (Starr and Hilton, 1999; Sasaki et al., 2000; Stofega et
al., 2000).
JAK2 was first identified in 1993 (Harpur et al., 1992) and was found to be
an essential mediator for erythropoietin signaling (Witthuhn et al., 1993).
The JAK2 gene is located on chromosome 9p24. Genetic deletion of JAK2 results
in embryonic death due to lack of definitive erythropoiesis, and JAK2- deficient
hematopoietic progenitors do not respond to erythropoietin stimulation, suggesting
that JAK2 is the only JAK kinase responsible for erythropoietin receptor signaling
(Parganas et al., 1998).
In 2005, several independent groups identified a recurrent mutation in the JAK2
tyrosine kinase in most patients with PV, ET or PMF (Baxter et al., 2005; James
et al., 2005; Kralovics et al., 2005; Levine et al., 2005). Subsequently,
the mutation was also described in other myeloid neoplasms (Steensma et al.,
2005). JAK2V617F is an exon 14 G to T somatic mutation. This mutation is a guanine-to-thymidine
substitution, which results in a substitution of valine for phenylalanine at
codon 617 within the JH2 domain of JAK2 (JAK2V617F). The JH2 domain is believed
to be auto-inhibitory (Saharinen and Silvennoinen, 2002), and valine 617 plays
an important role in JAK2 kinase auto-inhibition (Lindauer et al., 2001). Thus,
the valine to phenylalanine substitution at codon 617 results in constitutive
kinase activity resulting in a gain-of-function mutation (Ihle and Gilliland,
2007). Studies have shown that expression of JAK2V617F results in transformation
of Ba/F3 cells to IL-3 independent growth, unlike wild-type JAK2 (James et al.,
2005). Similarly, coexpression of JAK2V617F and erythropoietin receptor, thrombopoietin
receptor (MPL), or granulocyte-macrophage colony stimulating factor (GM-CSF)
receptor (all homodimeric Type 1 cytokine receptors) result in cytokine independent
growth and activation of signal transduction (Lu et al., 2005). In addition,
expression of JAK2V617F, results in constitutive activation of downstream signaling
pathways including the JAK-STAT, PI3K/AKT and MAPK/ERK pathways (James et al.,
2005; Kralovics et al., 2005; Levine et al., 2005).
The JAK2V617F mutation has been reported in over 95% of patients with PV, 50%
of patients with ET or PMF, 20% in certain other MPNs including refractory anemia
with ring sideroblasts and thrombocytosis (RARS-T), and less than 5% in AML
or MDS (Renneville et al., 2006; Steensma et al., 2006; Verstovsek et al.,
2006). JAK2V617F is a somatically acquired mutation and a subset of patients
with PV are homozygous for the JAK2V617F allele as a result of mitotic recombination
and duplication of the mutant allele, known as uniparental disomy. Uniparental
disomy of chromosomal locus 9p24, including JAK2, had previously been noted
in PV (Kralovics et al., 2002), and later the JAK2V617F allele was identified
through analysis of the minimal region of uniparental disomy (Kralovics et al.,
2005). It has been shown that most patients with PV possess JAK2V617F homozygous
mutant erythroid progenitors, while most patients with ET possess only heterozygous
and wild-type erythroid colonies (Scott et al., 2006). These observations suggest
that mitotic recombination and JAK2V617F homozygosity is an early genetic event
in the development of PV, but not ET.
In humans, JAK2V617F mutation occurs at the stem cell level and is present in
hematopoietic stem cell progenitors (Baxter et al., 2005; Jamieson et al.,
2006). It is believed to be myeloid lineage specific because it is present in
erythroid and granulocyte-macrophage progenitors (Baxter et al., 2005; James
et al., 2005). However, some reports have suggested JAK2V617F clonal involvement
of B (Ishii et al., 2006), T (Ishii et al., 2006), and NK (Bellanne-Chantelot
et al., 2006) lymphocytes. These observations confirm the stem cell nature of
JAK2V617F MPN's.
In retroviral transplant mouse models JAK2V617F induces a PV-like phenotype:
erythrocytosis, low serum erythropoietin level, splenomegaly due to extramedullary
hematopoiesis, leukocytosis, megakaryocytic hyperplasia and ultimately evolution
to myelofibrosis (Lacout et al., 2006; Wernig et al., 2006). It has also been
shown that in JAK2V617F transgenic mice, manipulation of mutant gene expression
results in either an ET (lower expression compared with wild-type allele) or
PV phenotype with (equal expression) or without (higher expression) thrombocytosis
(Tiedt et al., 2008). Based on the above experiments, we observe that mutant
allele burden in patients with ET is significantly lower than that seen in patients
with either PV or PMF (Kittur et al., 2007; (Tefferi et al., 2007; Vannucchi
et al., 2007b; Tefferi et al., 2008). In PV, a higher allele burden is the
result of JAK2V617F homozygosity.
Although JAK2V617F is central to the pathogenesis of PV, ET, PMF, the presence
of the same allele in three clinically distinct MPN's suggests that there
might be additional inherited or acquired genetic predisposition. A familial
tendency has been reported in 72 families with at least two members with MPN's
that were tested for JAK2V617F (Bellanne-Chantelot et al., 2006). The presence
of JAK2V617F in these families ranged from some families in which all members
carried the mutation, to some in which none of the members with MPN had the
JAK2V617F mutation. This pattern is consistent with a two-hit hypothesis, with
an inherited genetic predisposition to MPN (Pardanani et al., 2006a).
There is further evidence to suggest that other somatic alleles are involved
along with JAK2V617F in the development of MPN's. It is noted that in
a subset of JAK2V617F positive MPN who transform to AML, the leukemic blasts
are JAK2V617F mutation negative (Theocharides et al., 2007).
Other reported JAK2 exon 14 mutations include D620E (PV, MPN, unclassifiable),
E627E (MPN, unclassifiable), C616Y (PV), V617F from c.1848_1849delinsCT (post-ET
MF) and V617F/C618R from c.1849 - 1852GTCT > TTTC (PV) (Grunebach et al.,
2006; Schnittger et al., 2006; Wong et al., 2007; Zhang et al., 2007).
A small proportion of patients with PV are JAK2V617F negative when tested by
sensitive allele-specific assays (Jones et al., 2005). However, in 2007, Scott
and colleagues identified a set of JAK2 exon 12 mutations in JAK2V617F-negative
patients with PV (Scott et al., 2007b). The majority of these cases were found
to harbor 1 of 4 exon 12 JAK2 mutant alleles: N542-E543del, F537-K539delinsL,
a point mutation that results in substitution of lysine for leucine at codon
539 (K539L), and H538QK539L. All four exon 12 mutant alleles induced cytokine-independent/hypersensitive
proliferation in erythropoietin receptor-expressing cell lines and constitutive
activation of JAK-STAT signalling (Scott et al., 2007b). In addition, JAK2K539L
induced a PV phenotype in a murine transplant model. Unlike JAK2V617F, JAK2
exon 12 mutations are only observed in JAK2V617F- negative PV (i.e. approximately
5% of all PV cases) (Scott et al., 2007a; Butcher et al., 2008), and are specific
to patients with isolated erythrocytosis without concomitant leukocytosis or
thrombocytosis.
Several other exon 12 mutation variants have been identified; R541 - E543delinsK,
I540 - E543delinsMK, V536-I546dup11, F537-I546dup10 + 547L and E543-D544del
(Percy et al., 2007; Butcher et al., 2008; Pietra et al., 2008).
Approximately 50% of ET and PMF patients are JAK2V617F negative. This led Pikman
and colleagues (Pikman et al., 2006) to study whether other genes in the JAK-STAT
signaling pathway might be mutated in JAK2V617F negative ET and PMF. This led
to the identification of mutations of the thrombopoietin receptor (MPL), which
substitute either leucine or lysine by tryptophan at codon 515. These mutations
occur in 10% of JAK2V617F negative PMF and in 2% of JAK2V617F negative ET, but
not observed in PV or other myeloid malignancies (Pardanani et al., 2006b).
The prognostic significance of the JAK2V617F mutation has not been precisely
delineated. In ET, the presence of JAK2V617F has been associated with advanced
age, higher hemoglobin level, higher leukocyte counts and lower platelet counts
(Antonioli et al., 2005; Campbell et al., 2005; Wolanskyj et al., 2005; Kittur
et al., 2007). In addition in mutation-positive patients with ET, JAK2V617F
allele burden has been directly correlated with leukocyte count, platelet count
and the presence of palpable splenomegaly (Kittur et al., 2007; Vannucchi et
al., 2007b). Although JAK2V617F mutant and wild- type patients differ in regards
to laboratory parameters and clinical features, there were no differences in
overall survival, or myelofibrotic and leukemic transformations. In PV, JAK2V617F
homozygous patients were noted to have a higher hemoglobin level, higher leukocyte
count, lower platelet count, and an increased incidence of pruritus but not
an increased risk of thrombosis (Vannucchi et al., 2007b). A similar set of
correlations were made for higher mutant allele burden in PV, measured by quantitative
assays (Tefferi et al., 2007; Vannucchi et al., 2007a). In PMF, the presence
of JAK2V617F was associated with older age at diagnosis, higher leukocyte count
and presence of pruritus (Tefferi et al., 2005). Furthermore, JAK2V617F “homozygous”
PMF patients displayed even higher leukocyte count and spleen size (Barosi et
al., 2007). In PMF, the presence of the JAK2V617F mutation is associated with
poorer overall survival (Campbell et al., 2006). However, these data suggest
that JAK2V617F mutational status may have prognostic significance in PV, ET
and PMF, but additional studies of large patient cohorts are needed to confirm
these findings.
The prevalence of JAK2 exon 12 is too low to enable accurate assessment of prognostic
impact. Nevertheless, JAK2 exon 12 mutations have been associated with a PV
phenotype that is more likely to present with isolated erythrocytosis (Scott
et al., 2007b; Pietra et al., 2008).
The discovery of the JAK2V617F mutation in 2005 has been pivotal to our understanding
of the pathogenesis of PV, ET and PMF. The subsequent discovery in 2007 of the
JAK2 exon 12 mutations in JAK2V617F negative PV suggests that activation of
the JAK-STAT pathway is important in the pathogenesis of JAK2V617F-negative
MPN. Understanding the molecular pathogenesis of diseases, such as bcr-abl in
CML, and now JAK2V617F in PV, ET, and PMF has led to the development of small
molecule inhibitors of JAK2.
Accordingly, a number of anti-JAK2 small molecule drugs have been tested in
preclinical models and some have been introduced into clinical trials (Pardanani
et al., 2007; Lasho et al., 2008; Pardanani, 2008). Preliminary results from
currently ongoing JAK2 inhibitor drug trials (INCB018424, XL019) suggest remarkable
activity in alleviating symptomatic splenomegaly and constitutional symptoms
in patients with primary or post-PV/ET myelofibrosis (Verstovsek, 2007a; Verstovsek,
2007b). Despite the discovery of JAK2 and MPL mutations there are several unanswered
questions regarding the etiology of PV, ET and PMF; how does a single disease
allele contribute to three distinct clinical disorders? Will JAK2 inhibitor
therapy offer clinical benefit to patients with PV, ET and PMF?
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Written | 2008-09 | Naseema Gangat, Ayalew Tefferi |
of Hematology, Mayo Clinic, Rochester, MN, United States |
Citation |
This paper should be referenced as such : |
Gangat, N ; Tefferi, A |
JAK2 mutations in myeloproliferative neoplasms |
Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):612-617. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://AtlasGeneticsOncology.org/Deep/JAK2mutationID20065.htm |
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