{"entity":{"id":"jak2","kind":"target","name":"JAK2","aka":[],"tldr":"The signalling enzyme that tells marrow cells to make red cells and platelets; a single mutation (V617F) leaves it switched on in most myeloproliferative neoplasms.","summary":"Janus kinase 2 transduces signals from EPO, TPO and GM-CSF receptors via STAT5. JAK2 V617F (2005) is present in ~95% of polycythaemia vera and ~60% of essential thrombocythaemia and primary myelofibrosis; CALR and MPL mutations activate the same pathway. Approved JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib) inhibit wild-type and mutant JAK2 alike, controlling symptoms and spleen without eliminating the clone. Mutant-selective (V617F pseudokinase) and type II inhibitors are in development. JAK2 fusions and mutations also occur in ALL (Ph-like) and Down-syndrome ALL.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Janus_kinase_2","links":[{"label":"Kralovics 2005 (NEJM)","url":"https://doi.org/10.1056/NEJMoa051113"},{"label":"Kucuk et al., Nat Commun 2015: activating STAT3 and STAT5B mutations in lymphomas derived from NK or gamma-delta T cells","url":"https://doi.org/10.1038/ncomms7025"},{"label":"Green et al., Blood 2010: selective 9p24.1 amplification and PD-1 ligand induction through JAK2 in Hodgkin lymphoma and mediastinal large B-cell lymphoma","url":"https://doi.org/10.1182/blood-2010-05-282780"},{"label":"Roemer et al., J Clin Oncol 2016: PD-L1 and PD-L2 genetic alterations in 108 classical Hodgkin lymphomas","url":"https://doi.org/10.1200/JCO.2016.66.4482"},{"label":"Steidl et al., Nature 2011: CIITA is a recurrent fusion partner in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma","url":"https://doi.org/10.1038/nature09754"},{"label":"Ansell et al., N Engl J Med 2015: nivolumab in relapsed or refractory Hodgkin lymphoma (23 patients)","url":"https://doi.org/10.1056/NEJMoa1411087"}],"tags":["gap-fill"],"related":[],"cancers":["myeloproliferative-neoplasms","all-leukemia","non-hodgkin-lymphoma"],"sections":[],"technologies":["kinase-inhibitors"],"targets":[],"drugs":["ruxolitinib","fedratinib","pacritinib","momelotinib","ropeginterferon-alfa-2b"],"companies":[],"institutions":[],"pathways":["pi3k-akt-mtor","chemical-carcinogenesis-receptor-activation","pancreatic-cancer-signalling","jak-stat","pd1-checkpoint","antigen-presentation-immunoediting"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-kralovics-n-engl-j-med"],"journals":[],"dependsOn":[],"notes":["Lymphoma, JAK-STAT, in NK/T-cell lymphoma and in Hodgkin lymphoma: STAT3 and STAT5B mutations lock the transcription factor in its phosphorylated form. The STAT5B N642H substitution increases the binding affinity of the phosphotyrosine for the mutant histidine, so the phosphorylated protein persists and binds its target sites far more, and the growth advantage it gives can be partly reversed by a JAK1/2 inhibitor in the laboratory (Kucuk 2015). In Hodgkin lymphoma and primary mediastinal B-cell lymphoma the pathway is switched on from the other end, by amplification of JAK2 inside the 9p24.1 amplicon and by loss of the brakes SOCS1 and PTPN1. Frequency: Activating STAT3 and STAT5B mutations across 51 NK/T-cell lymphomas and 43 gamma-delta T-cell lymphomas, with STAT5B N642H particularly frequent in the gamma-delta group (Kucuk 2015). JAK2 sits in the 9p24.1 amplicon in Hodgkin lymphoma and mediastinal large B-cell lymphoma, and its amplification raises both protein and activity and specifically induces PD-1 ligand transcription (Green 2010). What it changes about treatment: Not through an approved drug. JAK inhibitors have been tested in both settings without becoming standard; the practical consequence of the Hodgkin and mediastinal finding is that it explains why checkpoint blockade works there.","Lymphoma, 9p24.1 amplification of CD274, PDCD1LG2 and JAK2: The amplicon contains the genes for both PD-1 ligands and the kinase that induces them, so a single copy-number event raises the ligands twice over, by gene dose and by JAK2-driven transcription (Green 2010). It is the clearest example in oncology of a tumour genetically buying its way out of T-cell attack. Alongside it, CIITA, the master transactivator of MHC class II, is broken by recurrent fusions, which lowers class II on the tumour cell and, in the same rearrangements, places PD-L1 and PD-L2 under new promoters. Frequency: In 108 newly diagnosed classical Hodgkin lymphomas evaluated by fluorescence in situ hybridisation, 97% had concordant alterations of both loci: polysomy in 5% (5 of 108), copy gain in 56% (61 of 108) and amplification in 36% (39 of 108), and higher-level gain predicted shorter progression-free survival (Roemer 2016). Genomic CIITA breaks in 38% of primary mediastinal B-cell lymphomas and 15% of classical Hodgkin lymphomas across 263 B-cell lymphomas (Steidl 2011). What it changes about treatment: Yes, and it is the reason for the sharpest contrast in lymphoma immunotherapy. PD-1 blockade produced an objective response in 20 of 23 heavily pre-treated Hodgkin patients, 87%, in the first study, in a disease where most had already failed both transplant and brentuximab vedotin (Ansell 2015); in B-cell non-Hodgkin lymphoma outside the mediastinal group, single-agent checkpoint blockade does very little. Nothing is tested before a Hodgkin patient is given a checkpoint inhibitor, because the alteration is nearly universal."],"symbol":"JAK2","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"few-types","specificityNote":"Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 6 medicines aimed at it (Ruxolitinib, Fedratinib, Pacritinib and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA JAK2: RNA low tissue specificity; blood lineage lineage enriched (granulocytes 133 nTPM); high antibody staining in 5 normal tissues; highest cancer staining lymphoma (9 of 12 high). Distribution: 2 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Myeloid neoplasms, Leukaemia); Open Targets associates it with 6 specific cancer types at or above 0.5 (acquired polycythemia vera, primary myelofibrosis, myelofibrosis, myeloproliferative disorder, acute myeloid leukemia, essential thrombocythemia). (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas JAK2 tissue","url":"https://www.proteinatlas.org/ENSG00000096968-JAK2/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000096968 associations","url":"https://platform.opentargets.org/target/ENSG00000096968/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:6192","ensembl":"ENSG00000096968","uniprot":"O60674","entrez":"3717","firstDescribed":1997,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Peeters et al, Blood, 1997, \"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\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/9326218/","biology":"JAK2 is a non-receptor tyrosine kinase with a pseudokinase (JH2) domain that normally restrains the kinase (JH1); V617F in JH2 relieves autoinhibition, causing cytokine-independent STAT5/MAPK/PI3K signalling and erythroid/megakaryocytic expansion.","whereFound":["Polycythaemia vera (~95% V617F, ~3% exon 12)","Essential thrombocythaemia and primary myelofibrosis (~55-65%)","Ph-like B-ALL (JAK2 fusions, ~7%)","Down syndrome ALL (JAK2 R683)"],"targetClass":"kinase","prevalence":[{"cancerId":"myeloproliferative-neoplasms","pct":"60-95","measure":"JAK2 V617F by subtype","source":"https://doi.org/10.1056/NEJMoa051113"}]},"route":"/targets/jak2/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"essential-thrombocythaemia","kind":"cancer","name":"Essential thrombocythaemia (ET)","route":"/cancers/essential-thrombocythaemia/"},{"id":"hodgkin-lymphoma","kind":"cancer","name":"Hodgkin lymphoma","route":"/cancers/hodgkin-lymphoma/"},{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"all-ph-like","kind":"cancer","name":"Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL)","route":"/cancers/all-ph-like/"},{"id":"polycythaemia-vera","kind":"cancer","name":"Polycythaemia vera (PV)","route":"/cancers/polycythaemia-vera/"},{"id":"primary-mediastinal-b-cell-lymphoma","kind":"cancer","name":"Primary mediastinal (thymic) large B-cell lymphoma","route":"/cancers/primary-mediastinal-b-cell-lymphoma/"},{"id":"primary-myelofibrosis","kind":"cancer","name":"Primary myelofibrosis","route":"/cancers/primary-myelofibrosis/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"drug":[{"id":"fedratinib","kind":"drug","name":"Fedratinib","route":"/drugs/fedratinib/"},{"id":"inca033989","kind":"drug","name":"INCA033989","route":"/drugs/inca033989/"},{"id":"momelotinib","kind":"drug","name":"Momelotinib","route":"/drugs/momelotinib/"},{"id":"pacritinib","kind":"drug","name":"Pacritinib","route":"/drugs/pacritinib/"},{"id":"ropeginterferon-alfa-2b","kind":"drug","name":"Ropeginterferon alfa-2b","route":"/drugs/ropeginterferon-alfa-2b/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"chemical-carcinogenesis-receptor-activation","kind":"pathway","name":"Chemical carcinogenesis - receptor activation","route":"/pathways/chemical-carcinogenesis-receptor-activation/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/"},{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"}],"paper":[{"id":"paper-kralovics-n-engl-j-med","kind":"paper","name":"A gain-of-function mutation of JAK2 in myeloproliferative disorders","route":"/key-papers/paper-kralovics-n-engl-j-med/"},{"id":"paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","kind":"paper","name":"COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis","route":"/key-papers/paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012/"},{"id":"paper-darnell-jak-stat-science-1994","kind":"paper","name":"Darnell, Kerr and Stark 1994: JAK-STAT pathways and transcriptional activation by interferons","route":"/key-papers/paper-darnell-jak-stat-science-1994/"},{"id":"paper-momentum-momelotinib-lancet-2023","kind":"paper","name":"MOMENTUM: momelotinib versus danazol for myelofibrosis patients with anaemia after a prior JAK inhibitor","route":"/key-papers/paper-momentum-momelotinib-lancet-2023/"}],"term":[{"id":"erythrocytosis","kind":"term","name":"Erythrocytosis (primary vs secondary)","route":"/terms/erythrocytosis/"},{"id":"ipset-thrombosis","kind":"term","name":"IPSET-thrombosis score (essential thrombocythaemia)","route":"/terms/ipset-thrombosis/"},{"id":"jak2-v617f","kind":"term","name":"JAK2 V617F","route":"/terms/jak2-v617f/"},{"id":"mpn-driver-mutations","kind":"term","name":"MPN driver mutations (JAK2 V617F, CALR, MPL) and allele burden","route":"/terms/mpn-driver-mutations/"},{"id":"lymphoma-bio-hodgkin-microenvironment","kind":"term","name":"The Hodgkin microenvironment: when the cancer cell is the minority","route":"/terms/lymphoma-bio-hodgkin-microenvironment/"}],"biomarker":[{"id":"pd-ligand-9p24-alteration","kind":"biomarker","name":"9p24.1 alteration of the PD-1 ligand loci","route":"/biomarkers/pd-ligand-9p24-alteration/"}],"target":[{"id":"acvr1","kind":"target","name":"ACVR1 (ALK2)","route":"/targets/acvr1/"},{"id":"brd4","kind":"target","name":"BRD4","route":"/targets/brd4/"},{"id":"epor","kind":"target","name":"Erythropoietin receptor (EPOR)","route":"/targets/epor/"},{"id":"csf3r","kind":"target","name":"G-CSF receptor (CSF3R)","route":"/targets/csf3r/"},{"id":"csf2ra","kind":"target","name":"GM-CSF receptor (CSF2RA)","route":"/targets/csf2ra/"},{"id":"il11ra","kind":"target","name":"IL-11 receptor alpha","route":"/targets/il11ra/"},{"id":"jak1","kind":"target","name":"JAK1","route":"/targets/jak1/"},{"id":"mpl","kind":"target","name":"MPL (thrombopoietin receptor)","route":"/targets/mpl/"},{"id":"stat5","kind":"target","name":"STAT5 (STAT5A, STAT5B)","route":"/targets/stat5/"}],"idea":[{"id":"idea-pv-clone-directed-therapy","kind":"idea","name":"Clearing the JAK2 clone in polycythaemia vera: interferon plus mutant-selective inhibitors as a route to treatment-free remission","route":"/ideas/idea-pv-clone-directed-therapy/"}],"trial":[{"id":"keynote-170","kind":"trial","name":"KEYNOTE-170","route":"/trials/keynote-170/"}]}}