Other entities represented in this entry:
HGNC Approved Gene Symbol: JAK2
Cytogenetic location: 9p24.1 Genomic coordinates (GRCh38): 9:4,984,390-5,129,948 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p24.1 | {Budd-Chiari syndrome, somatic} | 600880 | 3 | |
| Erythrocytosis, somatic | 133100 | 3 | ||
| Leukemia, acute myeloid, somatic | 601626 | 3 | ||
| Myelofibrosis, somatic | 254450 | 3 | ||
| Polycythemia vera, somatic | 263300 | 3 | ||
| Thrombocythemia 3 | 614521 | Autosomal dominant; Somatic mutation | 3 |
JAK2 kinase is a member of a family of tyrosine kinases involved in cytokine receptor signaling. See 147795 for background information on Janus kinases.
By screening a human placenta cDNA library with a probe encoding the catalytic domain of rat Jak2, followed by EST database searching, Saltzman et al. (1998) obtained a cDNA encoding a full-length JAK2 sequence. The JAK2 gene encodes a 1,132-amino acid protein that shares 95% sequence similarity to rat and pig Jak2. Northern blot analysis detected expression of 3 transcripts of 7.6, 5.9 and 4.8 kb in all tissues tested except heart and skeletal muscle. Highest expression was found in spleen, peripheral blood leukocytes, and testis. In heart and skeletal muscle, significant expression of 7.6-, 4.8-, and 3.9-kb transcripts was found.
By fluorescence resonance energy transfer (FRET), Brooks et al. (2014) elucidated the mechanism of activation of protein kinase JAK2 by the growth hormone receptor (GHR; 600946). Brooks et al. (2014) found that GHR exists predominantly as a dimer in vivo, held together by its transmembrane helices. These helices are parallel in the basal state, and binding of the hormone converts them into a left-hand crossover state that induces separation of helices at the lower transmembrane boundary. This movement is triggered by increased proximity of the juxtamembrane sequences, a consequence of locking together of the lower module of the extracellular domain on hormone binding. The key outcome is the separation of the Box1 sequences. Because these sequences are bound to the JAK2 FERM domains, this separation results in removal of the pseudokinase inhibitory domain of 1 JAK2, which is blocking the kinase domain of the other JAK2, and vice versa. This brings the 2 kinase domains into productive apposition, triggering JAK2 activation. Brooks et al. (2014) verified this mechanism by kinase-pseudokinase domain swap, by changes in JAK2 FRET signal on activation, by showing association of pseudokinase-kinase domain pairs, and by docking of the crystal structures.
Pritchard et al. (1992) mapped the JAK2 gene to chromosome 9p24 by in situ hybridization. Gough et al. (1995) mapped the homologous gene (Jak2) to mouse chromosome 19 in a region of homology of synteny to human 9.
Campbell et al. (1994) presented evidence that JAK2 is constitutively associated with the prolactin receptor (PRLR; 176761) and that it is activated and tyrosine phosphorylated upon PRL binding to the PRL receptor. These results are consistent with JAK2 serving as an early, perhaps initial, signaling molecule for prolactin.
Watling et al. (1993) isolated a cell line, selected for its inability to express interferon (IFN)-gamma (147570)-inducible cell-surface markers. The cell line was deficient in all aspects of IFN-gamma response tested but responded normally to alpha and beta IFNs (see 147660). The mutant cells could be complemented by the expression of JAK2. Unlike IFNs alpha and beta, IFN-gamma induced rapid tyrosine phosphorylation of JAK2 in wildtype cells, and JAK2 immunoprecipitates from these cells showed tyrosine kinase activity. These responses were absent in the mutant cell line. JAK2 is, therefore, required for the response to interferon-gamma but not to IFNs alpha and beta.
Saltzman et al. (1998) demonstrated that JAK2 phosphorylates STAT1 (600555), STAT2 (600556), STAT3 (102582), STAT4 (600558), and STAT5 (see STAT5A, 601511, and STAT5B, 604260), but not STAT6 (601512).
STAT5 is activated in a broad spectrum of human hematologic malignancies. Using a genetic approach, Schwaller et al. (2000) addressed whether activation of STAT5 is necessary for the myelo- and lymphoproliferative disease induced by the TEL (600618)/JAK2 fusion gene. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL/JAK2 developed a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5a/b-deficient mice expressing TEL/JAK2 did not induce disease. Disease induction in the Stat5a/b-deficient background was rescued with a bicistronic retrovirus encoding TEL/JAK2 and Stat5a. Furthermore, myeloproliferative disease was induced by reconstitution with bone marrow cells expressing a constitutively active mutant, Stat5a, or a single Stat5a target, murine oncostatin M (OSM; 165095). These data defined a critical role for STAT5A/B and OSM in the pathogenesis of TEL/JAK2 disease.
In addition to its role as a kidney cytokine regulating hematopoiesis, erythropoietin (133170) is also produced in the brain after oxidative or nitrosative stress. The transcription factor HIF1 (603348) upregulates erythropoietin following hypoxic stimuli. Digicaylioglu and Lipton (2001) demonstrated that preconditioning with erythropoietin protects neurons in models of ischemic and degenerative damage due to excitotoxins and consequent generation of free radicals, including nitric oxide. Activation of neuronal erythropoietin receptors (EPOR; 133171) prevents apoptosis induced by NMDA or nitric oxide by triggering crosstalk between the signaling pathways JAK2 and NFKB (see 164011). Digicaylioglu and Lipton (2001) demonstrated that erythropoietin receptor-mediated activation of JAK2 leads to phosphorylation of the inhibitor of NFKB (I-kappa-B-alpha; 164008), subsequent nuclear translocation of the transcription factor NFKB, and NFKB-dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of JAK2 or an I-kappa-B-alpha superrepressor blocks erythropoietin-mediated prevention of neuronal apoptosis. Thus, neuronal erythropoietin receptors activate a neuroprotective pathway that is distinct from previously well characterized JAK and NFKB functions. Moreover, this erythropoietin effect may underlie neuroprotection mediated by hypoxic-ischemic preconditioning.
Huang et al. (2001) showed that JAK2, and more specifically just its intact N-terminal domain, binds to EPOR in the endoplasmic reticulum and promotes its cell surface expression. This interaction was specific, as JAK1 had no effect. Residues 32 to 58 of the JAK2 JH7 domain were required for EPOR surface expression. Alanine scanning mutagenesis of the EPOR membrane proximal region revealed 2 modes of EPOR-JAK2 interaction. A continuous block of EPOR residues was required for functional, ligand-independent binding to JAK2 and cell surface receptor expression, whereas 4 specific residues were essential in switching on prebound JAK2 after ligand binding. Thus, in addition to its kinase activity required for cytokine receptor signaling, JAK is also an essential subunit required for surface expression of cytokine receptors.
Dawson et al. (2009) showed that human JAK2 is present in the nucleus of hematopoietic cells and directly phosphorylates tyr41 (Y41) on histone H3 (see 602810). Heterochromatin protein 1-alpha (HP1-alpha, 604478), but not HP1-beta (604511), specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukemic cells decreases both the expression of hematopoietic oncogene LMO2 (180385) and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1-alpha at the same site. Dawson et al. (2009) concluded that their results identified a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and revealed a direct mechanistic link between 2 genes, JAK2 and LMO2, involved in normal hematopoiesis and leukemia.
Mullighan et al. (2009) reported a recurring interstitial deletion of pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL (613035) that juxtaposes the first, noncoding exon of P2RY8 (300525) with the coding region of CRLF2 (300357). They identified the P2RY8/CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8/CRLF2 together with mutated mouse Jak2 resulted in constitutive JAK-STAT activation and cytokine-independent growth of Ba/F3 cells overexpressing IL7 receptor-alpha (IL7R; 146661). Mullighan et al. (2009) concluded that rearrangement of CRLF2 and JAK mutations together contribute to leukemogenesis in B-progenitor ALL.
Wilmes et al. (2020) quantified the dimerization of 3 prototypic class I cytokine receptors, thrombopoietin receptor (TPOR; 159530), erythropoietin receptor (EPOR; 133171), and GH receptor (GHR; 600946), in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated JAK2 dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.
Gong et al. (2021) confirmed that the JAK2 inhibitor TG101209 significantly inhibited proliferation and migration of basal-like breast cancer (BLBC) cells and induced apoptosis. Knockdown analysis showed that ZSWIM4 (620539) modulated sensitivity of BLBC cells to TG101209 treatment and that ZSWIM4 upregulation was responsible for JAK2 inhibition resistance. Knockdown of ZSWIM4 effectively overcame JAK2 inhibition resistance in BLBC cells. ZSWIM4 also conferred JAK2 inhibition resistance to luminal breast cancer cells. The authors identified VDR (601769) as a downstream effector of ZSWIM4-mediated drug resistance. Treatment with GW0742, a small-molecule compound that inhibits the transcriptional response regulated by VDR, could overcome the resistance of breast cancer cells to TG101209. Further analysis revealed that stable TG101209-resistant BLBC clones were sensitive to combined treatment with TG101209 and GW0742, suggesting that such combined treatment might be applicable for multiple solid tumors.
Polycythemia vera (263300), thrombocythemia (THCYT3; 614521), and idiopathic myelofibrosis (254450) are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on chromosome 9p in myeloproliferative disorders suggested that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases. Baxter et al. (2005) and Kralovics et al. (2005) found that a high proportion of patients with these myeloproliferative disorders carried a dominant somatic gain-of-function val617-to-phe mutation in the JAK2 gene (V617F; 147796.0001).
James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.
Using granulocyte-based mutation screening in 220 patients with either polycythemia vera or myelofibrosis with myeloid metaplasia, Tefferi et al. (2005) identified 21 patients who were homozygous for the V617F mutation of JAK2; 13 had polycythemia vera and 8 had myelofibrosis with myeloid metaplasia. Kralovics et al. (2005) proposed a 2-step model for the role of JAK2 (V617F) in the clonal evolution of myeloproliferative disorders. The first step consists, in their view, of a G-to-T mutation in 1 allele of the JAK2 gene that is acquired as a somatic mutation in a hematopoietic progenitor cell or stem cell. This cell gives rise to a clone that is heterozygous for V617F and expands to replace hematopoietic cells without the JAK2 mutation. The second step consists of a mitotic recombination in 1 of the progenitor cells or stem cells heterozygous for the JAK2 mutation that generates uniparental disomy and homozygosity for JAK2 (V617F) in 1 of the 2 daughter cells. This daughter cell gives rise to a clone that is homozygous for V617F and expands to replace heterozygous hematopoietic cells.
Lee et al. (2006) identified heterozygosity for mutations in the JAK2 gene (V617F and K607N, 147796.0002) in bone marrow aspirates from 3 (2.7%) of 113 unrelated patients with acute myelogenous leukemia (AML; 601626). JAK2 mutations were not found in 94 ductal breast carcinomas, 104 colorectal carcinomas, or 217 nonsmall cell lung cancers.
Scott et al. (2007) searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT; see 600555) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis (see 133100). They identified 4 somatic gain-of-function mutations affecting exon 12 of JAK2 in 10 of the V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3 (147740). They also exhibited increased phosphorylation of JAK2 and extracellular signal-regulated kinase 1 (ERK1; 176872) and 2 (ERK2; 176948), as compared with cells transduced by wildtype JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2 (147796.0003). This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation.
Bercovich et al. (2008) identified somatic JAK2 mutations in 16 (18%) of 88 patients with Down syndrome (190685)-associated acute lymphoblastic leukemia (ALL). Only 1 of 109 patients with non-Down syndrome-associated leukemia had the mutation, but this child was also found to have an isochromosome 21q. All the JAK2-associated leukemias were of the B-cell precursor type. Children with a JAK2 mutation were younger (mean age, 4.5 years) compared to patients without JAK2 mutations (8.6 years) at diagnosis. Five mutant JAK2 alleles were identified, each affecting a highly conserved residue: arg683 (i.e., R683G, R683S, R683K). In vitro functional expression studies in mouse hematopoietic progenitor cells showed that the mutations caused constitutive Jak/Stat activation and cytokine-independent growth, consistent with a gain of function. This growth was sensitive to pharmacologic inhibition with a JAK inhibitor. Modeling studies showed that arg683 is located in an exposed conserved region of the JAK2 pseudokinase domain in a region different from that implicated in myeloproliferative disorders. Bercovich et al. (2008) concluded that there is a specific association between constitutional trisomy 21 and arg683 JAK2 mutations that predisposes to the development of B-cell ALL in patients with Down syndrome.
Germline JAK2 Mutation
In a case-control study of unexplained pregnancy loss (see 614389), Mercier et al. (2007) found association between the JAK2 V617F mutation and the risk of fetal or embryonic loss. However, Dahabreh et al. (2008) found no evidence for increased prevalence of the JAK2 V617F mutation in women with a history of recurrent miscarriage.
By genomewide analysis of 181 individuals with polycythemia vera or essential thrombocytosis, Kilpivaara et al. (2009) identified a C-G transversion in intron 12 (rs10974944) that predisposed to the development of V617F-positive myeloproliferative neoplasms. The minor G allele of this SNP was significantly more common among 324 individuals with polycythemia vera, essential thrombocythemia, or primary myelofibrosis, compared to controls (odds ratio of 3.1; p = 4.1 x 10(-20)). The V617F mutation was preferentially acquired in cis with the predisposition allele. These data suggested that germline variations are an important contributor to myeloproliferative phenotype and predisposition associated with somatic mutations.
Jones et al. (2009) found that 109 (77%) of 142 alleles harboring the JAK2 V617F mutation from patients with a myeloproliferative neoplasm had the JAK2 46/1 haplotype, which was tagged by rs12343867 in intron 14 and rs12340895, compared to only 9 (12%) of the 74 residual wildtype alleles (p = 1.4 x 10(-20)). The results indicated that homozygosity for V617F was not random, but rather occurred preferentially when this mutation was present on the specific JAK2 haplotype. Additional analysis in 177 heterozygous V617F carriers found that V617F occurred more frequently on the 46/1 haplotype (135 of 354 alleles) compared to 188 controls (92 of 376 alleles; p = 0.0001) and 1,500 controls (p = 3.3 x 10(-8)). Sequencing of the products in 66 informative cases showed that 49 (74%) V617F alleles arose on the 46/1 allele, whereas only 17 (26%) wildtype alleles were on 46/1 (p = 2.1 x 10(-8)). V617F-associated disease was strongly associated with haplotype 46/1 in all 3 disease entities compared to healthy controls: polycythemia vera (p = 2.9 x 10(-16)), essential thrombocythemia (p = 8.2 x 10(-9)), and myelofibrosis (p = 8.0 x 10(-5)). Jones et al. (2009) concluded that the 46/1 haplotype predisposes to the development of V617F-associated myeloproliferative neoplasms, with an overall odds ratio of 3.7.
Olcaydu et al. (2009) also found that a JAK2 haplotype including rs12343867 preferentially acquired the V617F mutation and conferred susceptibility to myeloproliferative disorders. Ninety-three (85%) of 109 individuals with myeloproliferative disorders who were heterozygous for rs12343867 carried the V617F mutation on the C allele (p = 7.8 x 10(-15)). Olcaydu et al. (2009) suggested that a certain combination of SNPs may render haplotypes differentially susceptible to somatic mutagenesis.
In affected members of a family with autosomal dominant thrombocythemia-3 (THCYT3; 614521), Mead et al. (2012) identified a germline heterozygous G-to-A transition in the JAK2 gene, resulting in a val617-to-ile (V617I) substitution. The proband presented at age 53 years with an ischemic cerebrovascular event associated with long-standing thrombocytosis (700 x 10(9) to 970 x 10(9)). There were 5 additional family members with thrombocytosis, including 1 with a myocardial infarction at age 46 and another with a myocardial infarction at age 65 and an ischemic cerebrovascular event at age 72. Bone marrow biopsy showed megakaryocyte hyperplasia without fibrosis. In addition, none of the patients had splenomegaly or evidence of leukemic transformation. Examination of peripheral blood cells showed normal baseline STAT3 (102582) activity and lack of cytokine-independent colony formation. However, after stimulation with granulocyte colony-stimulating factor (GCSF; 138970), V617I-containing CD33+ myeloid and CD34+ stem cells showed a marked increase in STAT3 levels, particularly in response to low levels of GCSF, suggesting that the mutation causes limited constitutive activation with a reduced threshold for cytokine-induced activation.
ETV6/JAK2 Fusion Gene
Peeters et al. (1997) identified a t(9;12)(p24;p13) translocation in a patient with early pre-B acute lymphoid leukemia and a t(9;15;12)(p24;q15;p13) translocation in a patient with atypical chronic myelogenous leukemia (CML; 608232) in transformation. Both changes involved the ETV6 gene (600618) at 12p13 and the JAK2 gene at 9p24. In each case different fusion mRNAs were found, with only 1 resulting in a chimeric protein consisting of the oligomerization domain of ETV6 and the protein tyrosine kinase domain of JAK2.
Lacronique et al. (1997) observed a t(9;12)(p24;p13) translocation in leukemic cells from a 4-year-old boy with T-cell ALL. The 3-prime portion of the JAK2 gene was fused to the 5-prime portion of the ETV6 gene, resulting in a protein containing the catalytic domain of JAK2 and the oligomerization domain of ETV6. The resultant protein had constitutive tyrosine kinase activity and conferred cytokine-independent proliferation to a murine cell line.
To assess the role of JAK2, Parganas et al. (1998) derived Jak2-deficient mice by targeted disruption of the mouse gene in embryonic stem cells. The mutation caused an embryonic lethality due to the absence of definitive erythropoiesis. Fetal liver myeloid progenitors, although present based on the expression of lineage-specific markers, failed to respond to erythropoietin, thrombopoietin (600044), interleukin-3 (147740), or granulocyte/macrophage colony-stimulating factor (138960). In contrast, the response to granulocyte-specific colony-stimulating factor was unaffected. Jak2-deficient fibroblasts failed to respond to IFN-gamma, although the responses to IFN-alpha/beta and interleukin-6 (147620) were unaffected. Reconstitution experiments demonstrated that Jak2 was not required for the generation of lymphoid progenitors, their amplification, or their functional differentiation. Parganas et al. (1998) concluded that Jak2 plays a critical, nonredundant role in the function of a specific group of cytokine receptors.
Neubauer et al. (1998) also performed a targeted inactivation of Jak2 in mice. Jak2 -/- embryos were anemic and died around day 12.5 postcoitum. Primitive erythrocytes were found, but definitive erythropoiesis was absent. Compared to erythropoietin receptor-deficient mice, the phenotype of Jak2 deficiency was more severe. Fetal liver BFU-E and CFU-E colonies were completely absent. However, multilineage hematopoietic stem cells (CD34-low, c-kit-pos) were found, and B lymphopoiesis appeared intact. In contrast to IFN-alpha stimulation, Jak2 -/- cells did not respond to IFN-gamma. Jak2 -/- embryonic stem cells were competent for LIF signaling. These data also demonstrated that Jak2 has pivotal functions for signal transduction of a set of cytokine receptors required in definitive erythropoiesis.
Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis
In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells.
In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia.
James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.
Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490.
An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers.
Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which renders the kinase constitutively active, leading to uncontrolled cell expansion. Mendez-Ferrer et al. (2008) and Mendez-Ferrer et al. (2010) showed that bone marrow nestin (NES; 600915)-positive mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibers regulate normal HSCs. Arranz et al. (2014) demonstrated that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibers, supporting Schwann cells and nestin-positive MSCs, were consistently reduced in the bone marrow of MPN patients and mice expressing the human V617F mutation in the JAK2 gene in HSCs. Unexpectedly, MSC reduction was not due to differentiation but to bone marrow neural damage and Schwann cell death triggered by IL1B (147720) produced by mutant HSCs. In turn, in vivo depletion of nestin-positive cells or their production of CXCL12 (600835) expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with beta-3-adrenergic agonists that restored the sympathetic regulation of nestin-positive MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukemic stem cells. Arranz et al. (2014) concluded that their results demonstrated that mutant HSC-driven niche damage critically contributes to disease manifestations in MPNs, and identified niche-forming MSCs and their neural regulation as therapeutic targets.
Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms.
Acute Myelogeneous Leukemia
Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy.
Susceptibility to Pregnancy Loss
Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009).
Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage.
Budd-Chiari Syndrome
Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder.
Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients.
In bone marrow aspirate from 1 of 113 patients with acute myelogenous leukemia (AML; 601626), Lee et al. (2006) identified a heterozygous 1821G-C transversion in the twelfth coding exon (exon 14) of the JAK2 gene, resulting in a lys607-to-asn (K607N) substitution in a conserved residue in the pseudokinase domain.
Among 10 patients with a diagnosis of polycythemia vera or idiopathic erythrocytosis (see 133100) who did not carry the V617F mutation in JAK2 (147796.0001), Scott et al. (2007) found 3 alleles carrying a somatic lys539-to-leu substitution (K539L) in exon 12 of the JAK2 gene. Those with this and 3 other JAK2 exon 12 mutations presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occurred in most patients with V617F-positive polycythemia vera. The K539L mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation.
In affected members of a family with autosomal dominant thrombocythemia-3 (THCYT3; 614521), Mead et al. (2012) identified a germline heterozygous G-to-A transition in the JAK2 gene, resulting in a val617-to-ile (V617I) substitution. The proband presented at age 53 years with an ischemic cerebrovascular event associated with long-standing thrombocytosis (700 x 10(9) to 970 x 10(9)). There were 5 additional family members with thrombocytosis, including 1 with a myocardial infarction at age 46 and another with a myocardial infarction at age 65 and an ischemic cerebrovascular event at age 72. Bone marrow biopsy showed megakaryocyte hyperplasia without fibrosis. In addition, none of the patients had splenomegaly or evidence of leukemic transformation. Examination of peripheral blood cells showed normal baseline STAT3 (102582) activity and lack of cytokine-independent colony formation. However, after stimulation with (GCSF; 138970), V617I-containing CD33+ myeloid and CD34+ stem cells showed a marked increase in STAT3 levels, particularly in response to low levels of GCSF, suggesting that the mutation causes limited constitutive activation with a reduced threshold for cytokine-induced activation.
Arranz, L., Sanchez-Aguilera, A., Martin-Perez, D., Isern, J., Langa, X., Tzankov, A., Lundberg, P., Muntion, S., Tzeng, Y.-S., Lai, D.-M., Schwaller, J., Skoda, R. C., Mendez-Ferrer, S. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512: 78-81, 2014. [PubMed: 25043017] [Full Text: https://doi.org/10.1038/nature13383]
Baxter, E. J., Scott, L. M., Campbell, P. J., East, C., Fourouclas, N., Swanton, S., Vassiliou, G. S., Bench, A. J., Boyd, E. M., Curtin, N., Scott, M. A., Erber, W. N., Cancer Genome Project, Green, A. R. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365: 1054-1061, 2005. Note: Erratum: Lancet 366: 122 only, 2005. [PubMed: 15781101] [Full Text: https://doi.org/10.1016/S0140-6736(05)71142-9]
Bercovich, D., Ganmore, I., Scott, L. M., Wainreb, G., Birger, Y., Elimelech, A., Shochat, C., Cazzaniga, G., Biandi, A., Basso, G., Cario, G., Schrapper, M., and 17 others. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 372: 1484-1492, 2008. [PubMed: 18805579] [Full Text: https://doi.org/10.1016/S0140-6736(08)61341-0]
Brooks, A. J., Dai, W., O'Mara, M. L., Abankwa, D., Chhabra, Y., Pelekanos, R. A., Gardon, O., Tunny, K. A., Blucher, K. M., Morton, C. J., Parker, M. W., Sierecki, E., Gambin, Y., Gomez, G. A., Alexandrov, K., Wilson, I. A., Doxastakis, M., Mark, A. E., Waters, M. J. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344: 1249783, 2014. Note: Electronic Article. [PubMed: 24833397] [Full Text: https://doi.org/10.1126/science.1249783]
Campbell, G. S., Argetsinger, L. S., Ihle, J. N., Kelly, P. A., Rillema, J. A., Carter-Su, C. Activation of JAK2 tyrosine kinase by prolactin receptors in Nb2 cells and mouse mammary gland explants. Proc. Nat. Acad. Sci. 91: 5232-5236, 1994. [PubMed: 7515493] [Full Text: https://doi.org/10.1073/pnas.91.12.5232]
Campbell, P. J., Scott, L. M., Buck, G., Wheatley, K., East, C. L., Marsden, J. T., Duffy, A., Boyd, E. M., Bench, A. J., Scott, M. A., Vassiliou, G. S., Milligan, D. W., Smith, S. R., Erber, W. N., Bareford, D., Wilkins, B. S., Reilly, J. T., Harrison, C. N., Green, A. R. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 366: 1945-1953, 2005. [PubMed: 16325696] [Full Text: https://doi.org/10.1016/S0140-6736(05)67785-9]
Chung, R. T., Iafrate, A. J., Amrein, P. C., Sahani, D. V., Misdraji, J. Case 15-2006: a 46-year-old woman with sudden onset of abdominal distention. New Eng. J. Med. 354: 2166-2175, 2006. [PubMed: 16707754] [Full Text: https://doi.org/10.1056/NEJMcpc069006]
Dahabreh, I. J., Jones, A. V., Voulgarelis, M., Giannouli, S., Zoi, C., Alafakis-Tzannatos, C., Varla-Leftherioti, M., Moutsopoulos, H. M., Loukopoulos, D., Fotiou, S., Cross, N. C. P., Zoi, K. No evidence for increased prevalence of JAK2 V617F in women with a history of recurrent miscarriage. (Letter) Brit. J. Haemat. 144: 802-803, 2008. [PubMed: 19036091] [Full Text: https://doi.org/10.1111/j.1365-2141.2008.07510.x]
Dawson, M. A., Bannister, A. J., Gottgens, B., Foster, S. D., Bartke, T., Green, A. R., Kouzarides, T. JAK2 phosphorylates histone H3Y41 and excludes HP1-alpha from chromatin. Nature 461: 819-822, 2009. [PubMed: 19783980] [Full Text: https://doi.org/10.1038/nature08448]
Digicaylioglu, M., Lipton, S. A. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappa-B signalling cascades. Nature 412: 641-647, 2001. [PubMed: 11493922] [Full Text: https://doi.org/10.1038/35088074]
Gong, K., Song, K., Zhu, Z., Xiang, Q., Wang, K., Shi, J. SWIM domain protein ZSWIM4 is required for JAK2 inhibition resistance in breast cancer. Life Sci. 279: 119696, 2021. [PubMed: 34102191] [Full Text: https://doi.org/10.1016/j.lfs.2021.119696]
Gough, N. M., Rakar, S., Harpur, A., Wilks, A. F. Localization of genes for two members of the JAK family of protein tyrosine kinases to murine chromosomes 4 and 19. Mammalian Genome 6: 247-248, 1995. [PubMed: 7613027] [Full Text: https://doi.org/10.1007/BF00352409]
Huang, L. J., Constantinescu, S. N., Lodish, H. F. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Molec. Cell 8: 1327-1338, 2001. [PubMed: 11779507] [Full Text: https://doi.org/10.1016/s1097-2765(01)00401-4]
James, C., Ugo, V., Le Couedic, J.-P., Staerk, J., Delhommeau, F., Lacout, C., Garcon, L., Raslova, H., Berger, R., Bennaceur-Griscelli, A., Villeval, J. L., Constantinescu, S. N., Casadevall, N., Vainchenker, W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434: 1144-1148, 2005. [PubMed: 15793561] [Full Text: https://doi.org/10.1038/nature03546]
Jamieson, C. H. M., Gotlib, J., Durocher, J. A., Chao, M. P., Mariappan, M. R., Lay, M., Jones, C., Zehnder, J. L., Lilleberg, S. L., Weissman, I. L. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc. Nat. Acad. Sci. 103: 6224-6229, 2006. [PubMed: 16603627] [Full Text: https://doi.org/10.1073/pnas.0601462103]
Jones, A. V., Chase, A., Silver, R. T., Oscier, D., Zoi, K., Wang, Y. L., Cario, H., Pahl, H. L., Collins, A., Reiter, A., Grand, F., Cross, N. C. P. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nature Genet. 41: 446-449, 2009. [PubMed: 19287382] [Full Text: https://doi.org/10.1038/ng.334]
Kilpivaara, O., Mukherjee, S., Schram, A. M., Wadleigh, M., Mullally, A., Ebert, B. L., Bass, A., Marubayashi, S., Heguy, A., Garcia-Manero, G., Kantarjian, H., Offit, K., Stone, R. M., Gilliland, D. G., Klein, R. J., Levine, R. L. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nature Genet. 41: 455-459, 2009. [PubMed: 19287384] [Full Text: https://doi.org/10.1038/ng.342]
Kralovics, R., Cazzola, M., Skoda, R. C. Reply to Tefferi et al. (Letter) New Eng. J. Med. 353: 1417 only, 2005.
Kralovics, R., Passamonti, F., Buser, A. S., Teo, S.-S., Tiedt, R., Passweg, J. R., Tichelli, A., Cazzola, M., Skoda, R. C. A gain-of-function mutation of JAK2 in myeloproliferative disorders. New Eng. J. Med. 352: 1779-1790, 2005. [PubMed: 15858187] [Full Text: https://doi.org/10.1056/NEJMoa051113]
Lacronique, V., Boureux, A., Della Valle, V., Poirel, H., Quang, C. T., Mauchauffe, M., Berthou, C., Lessard, M., Berger, R., Ghysdael, J., Bernard, O. A. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278: 1309-1312, 1997. [PubMed: 9360930] [Full Text: https://doi.org/10.1126/science.278.5341.1309]
Lee, J. W., Kim, Y. G., Soung, Y. H., Han, K. J., Kim, S. Y., Rhim, H. S., Min, W. S., Nam, S. W., Park, W. S., Lee, J. Y., Yoo, N. J., Lee, S. H. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 25: 1434-1436, 2006. [PubMed: 16247455] [Full Text: https://doi.org/10.1038/sj.onc.1209163]
Mead, A. J., Rugless, M. J., Jacobsen, S. E. W. Schuh, A.: Germline JAK2 mutation in a family with hereditary thrombocytosis. (Letter) New Eng. J. Med. 366: 967-969, 2012. [PubMed: 22397670] [Full Text: https://doi.org/10.1056/NEJMc1200349]
Mendez-Ferrer, S., Lucas, D., Battista, M., Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452: 442-447, 2008. [PubMed: 18256599] [Full Text: https://doi.org/10.1038/nature06685]
Mendez-Ferrer, S., Michurina, T. V., Ferraro, F., Mazloom, A. R., MacArthur, B. D., Lira, S. A., Scadden, D. T., Ma'ayan, A., Enikolopov, G. N., Frenette, P. S. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466: 829-834, 2010. [PubMed: 20703299] [Full Text: https://doi.org/10.1038/nature09262]
Mercier, E., Lissalde-Lavigne, G., Gris, J.-C. JAK2 V617F mutation in unexplained loss of first pregnancy. (Letter) New Eng. J. Med. 357: 1984-1985, 2007. [PubMed: 17989398] [Full Text: https://doi.org/10.1056/NEJMc071528]
Mullighan, C. G., Collins-Underwood, J. R., Phillips, L. A. A., Loudin, M. G., Liu, W., Zhang, J., Ma, J., Coustan-Smith, E., Harvey, R. C., Willman, C. L., Mikhail, F. M., Meyer, J., and 12 others. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nature Genet. 41: 1243-1246, 2009. [PubMed: 19838194] [Full Text: https://doi.org/10.1038/ng.469]
Neubauer, H., Cumano, A., Muller, M., Wu, H., Huffstadt, U., Pfeffer, K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93: 397-409, 1998. [PubMed: 9590174] [Full Text: https://doi.org/10.1016/s0092-8674(00)81168-x]
Olcaydu, D., Harutyunyan, A., Jager, R., Berg, T., Gisslinger, B., Pabinger, I., Gisslinger, H., Kralovics, R. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nature Genet. 41: 450-454, 2009. [PubMed: 19287385] [Full Text: https://doi.org/10.1038/ng.341]
Ortmann, C. A., Kent, D. G., Nangalia, J., Silber, Y., Wedge, D. C., Grinfeld, J., Baxter, E. J., Massie, C. E., Papaemmanuil, E., Menon, S., Godfrey, A. L., Dimitropoulou, D., and 9 others. Effect of mutation order on myeloproliferative neoplasms. New Eng. J. Med. 372: 601-612, 2015. [PubMed: 25671252] [Full Text: https://doi.org/10.1056/NEJMoa1412098]
Parganas, E., Wang, D., Stravopodis, D., Topham, D. J., Marine, J.-C., Teglund, S., Vanin, E. F., Bodner, S., Colamonici, O. R., van Deursen, J. M., Grosveld, G., Ihle, J. N. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93: 385-395, 1998. [PubMed: 9590173] [Full Text: https://doi.org/10.1016/s0092-8674(00)81167-8]
Patel, R. K., Lea, N. C., Heneghan, M. A., Westwood, N. B., Milojkovic, D., Thanigaikumar, M., Yallop, D., Arya, R., Pagliuca, A., Gaken, J., Wendon, J., Heaton, N. D., Mufti, G. J. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology 130: 2031-2038, 2006. [PubMed: 16762626] [Full Text: https://doi.org/10.1053/j.gastro.2006.04.008]
Peeters, P., Raynaud, S. D., Cools, J., Wlodarska, I., Grosgeorge, J., Philip, P., Monpoux, F., Van Rompaey, L., Baens, M., Van den Berghe, H., Marynen, P. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 90: 2535-2540, 1997. [PubMed: 9326218]
Pritchard, M. A., Baker, E., Callen, D. F., Sutherland, G. R., Wilks, A. F. Two members of the JAK family of protein tyrosine kinases map to chromosomes 1p31.3 and 9p24. Mammalian Genome 3: 36-38, 1992. [PubMed: 1581631] [Full Text: https://doi.org/10.1007/BF00355839]
Saltzman, A., Stone, M., Franks, C., Searfoss, G., Munro, R., Jaye, M., Ivashchenko, Y. Cloning and characterization of human Jak-2 kinase: high mRNA expression in immune cells and muscle tissue. Biochem. Biophys. Res. Commun. 246: 627-633, 1998. [PubMed: 9618263] [Full Text: https://doi.org/10.1006/bbrc.1998.8685]
Schwaller, J., Parganas, E., Wang, D., Cain, D., Aster, J. C., Williams, I. R., Lee, C.-K., Gerthner, R., Kitamura, T., Frantsve, J., Anastasiadou, E., Loh, M. L., Levy, D. E., Ihle, J. N., Gilliland, D. G. Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Molec. Cell 6: 693-704, 2000. [PubMed: 11030348] [Full Text: https://doi.org/10.1016/s1097-2765(00)00067-8]
Scott, L. M., Tong, W., Levine, R. L., Scott, M. A., Beer, P. A., Stratton, M. R., Futreal, P. A., Erber, W. N., McMullin, M. F., Harrison, C. N., Warren, A. J., Gilliland, D. G., Lodish, H. F., Green, A. R. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. New Eng. J. Med. 356: 459-468, 2007. Note: Erratum: New Eng. J. Med. 357: 1457 only, 2007. [PubMed: 17267906] [Full Text: https://doi.org/10.1056/NEJMoa065202]
Sozer, S., Fiel, M. I., Schiano, T., Xu, M., Mascarenhas, J., Hoffman, R. The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood 113: 5246-5249, 2009. [PubMed: 19293426] [Full Text: https://doi.org/10.1182/blood-2008-11-191544]
Tefferi, A., Lasho, T. L., Gilliland, G. JAK2 mutations in myeloproliferative disorders. (Letter) New Eng. J. Med. 353: 1416-1417, 2005. [PubMed: 16192494] [Full Text: https://doi.org/10.1056/NEJMc051878]
Watling, D., Guschin, D., Muller, M., Silvennoinen, O., Witthuhn, B. A., Quelle, F. W., Rogers, N. C., Schindler, C., Stark, G. R., Ihle, J. N., Kerr, I. M. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature 366: 166-170, 1993. [PubMed: 7901766] [Full Text: https://doi.org/10.1038/366166a0]
Wilmes, S., Hafer, M., Vuorio, J., Tucker, J. A., Winkelmann, H., Lochte, S., Stanly, T. A., Pulgar Prieto, K. D., Poojari, C., Sharma, V., Richter, C. P., Kurre, R., Hubbard, S. R., Garcia, K. C., Moraga, I., Vattulainen, I., Hitchcock, I. S., Piehler, J. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science 367: 643-652, 2020. [PubMed: 32029621] [Full Text: https://doi.org/10.1126/science.aaw3242]