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JAK2 (janus kinase 2)
Sabine Strehl
Children's Cancer Research Institute, Kinderspitalgasse 6, A-1090 Vienna, Austria
Published in Atlas Database: September 2005
Online updated version: http://AtlasGeneticsOncology.org/Genes/JAK98.html
DOI: 10.4267/2042/38263
This article is an update of: Huret JL. JAK2 (janus kinase 2). Atlas Genet Cytogenet Oncol Haematol.1998;2(1):14.
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
PTK or TyrKc domain), and a tyrosine kinase-like
domain JH2 (also termed STYKc).
Hugo: JAK2
Location: 9p24
Expression
Wide.
Localisation
Intracellular, possibly membrane associated.
Function
Protein tyrosine kinase of the non-receptor type that
associates with the intracellular domains of cytokine
receptors; JAK2 is the predominant JAK kinase
activated in response to several growth factors and
cytokines such as IL-3, GM-CSF and erythropoietin; it
has been found to be constitutively associated with the
prolactin receptor and is required for responses to
gamma interferon.
Homology
JAK2 belongs to the janus kinase subfamily; so far four
mammalian JAKs have been identified (JAK1, JAK2,
JAK3, and TYK2); human JAK2 is >90% identical to
the mouse and the rat JAK2 homologs.
JAK2 (9p24) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Mutations
DNA/RNA
Somatic
Description
A high proportion (>50%) of patients with
myeloproliferative disorders (MPD; (polycythemia
vera,
essential
thrombocythemia,
idiopathic
myelofibrosis - see below) carry a dominant gain-offunction V617F mutation in the JH2 kinase-like
domain of JAK2. This mutation leads to deregulation
of the kinase activity, and thus to constitutive tyrosine
phosphorylation activity. The incidence of the V617F
mutation in different studies ranges from 65-97% in
polycythemia vera, from 41-57% in patients with
essential thrombocythemia, and from 23-95% in
25 exons spanning roughly 140 kb of genomic DNA;
5402 bp pre-mRNA; 6 different transcripts, putatively
encoding 4 different protein isoforms.
Protein
Description
1132 amino acids; 130,7 kDa; JAK2 contains a central
Src homology 2 (SH2) domain, and two C-terminal
domains: a tyrosine kinase domain JH1 (also termed
Atlas Genet Cytogenet Oncol Haematol. 2006;10(1)
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JAK2 (janus kinase 2)
Strehl S
patients with idiopathic myelofibrosis. In MPD the
mutation is heterozygous in most patients and
homozygous only in a minor subset. Mitotic
recombination probably causes both 9p LOH and the
transition from heterozygosity to homozygosity. The
same mutation was also found in roughly 20% of Phnegative atypical CML, in more than 10% of CMML,
in about 15% of patients with megakaryocytic AML
(AML M7), and 1/5 patients with juvenile
myelomonocytic leukemia (JMML). The V617F
mutation seems to occur exclusively in hematopietic
malignancies of the myeloid lineage.
Hybrid/Mutated Gene
5' ETV6 - 3' JAK2
Abnormal Protein
In the atypical CML the N-terminal HLH of ETV6 is
fused to the tyrosine kinase C-terminal domains (JH2
and JH1) of JAK2; in the B-ALL the same ETV6
domain is fused to part of the JH2 and the complete
JH1 domain, and in the T-ALL case to the JH1 domain.
Oncogenesis
It may be speculated that the HLH domain of ETV6
provides a dimerization interface to the kinase domain
of JAK2, which activates JAK2; ETV6-JAK2
transgenic mice - generated using a T-ALL specific
fusion construct - develop fatal CD8+ acute T-cell
leukemia.
Implicated in
t(8;9)(p21-22;p24)/acute leukaemias →
PCM1-JAK2
t(9;22)(p24;q11.2)/MPD→ JAK2-BCR
Disease
Myeloid and lymphoid malignancies; predominantly
atypical CML, but also found in chronic eosinophilic
leukemia (CEL), (secondary) AML, and MDS/MPD;
thirteen cases described to date, all male, except for one
childhood female case with erythroid leukemia with
multiple bone tumors.
Prognosis
Highly variable; allogeneic stem cell transplantation
may be the only curative treatment.
Hybrid/Mutated Gene
5’ PCM1 - 3’ JAK2; only in some cases the reciprocal
5’ JAK2 - 3’ PCM1 is present.
Abnormal Protein
Almost the entire PCM1 protein containing multiple
coiled-coil domains is fused to the tyrosine kinase Cterminal domains (JH2 and JH1) of JAK2.
Oncogenesis
Dimerization or oligomerization of the PCM1-JAK2
chimera through one or more of the coiled-coil motifs
of PCM1 probably results in the constitutive activation
of the tyrosine kinase domain of JAK2.
Disease
Atypical CML; only one case described to date.
Hybrid/Mutated Gene
5’ BCR - 3’ JAK2; absence of the reciprocal 5’ JAK2 3’ BCR.
Abnormal Protein
The N-terminal coiled-coil domain of BCR is fused to
the JH1 tyrosine kinase C-terminal domain of JAK2.
Oncogenesis
Constitutive activation of the tyrosine kinase domain of
JAK2 mediated through oligomerization through the
coiled-coil domain of BCR.
Polycythemia vera/Essential
thrombocythemia/Idiopathic
thrombocythemia/Idiopathic
myelofibrosis
Note: the V617F mutation in JAK2 could form the
basis for a new molecular classification of
myeloproliferative disorders.
Disease
Chronic myeloproliferative syndromes.
Oncogenesis
A significant percentage of patients
with
myeloproliferative disorders carries a dominant gain of
function V617F mutation in JAK2; this mutation seems
to lead to deregulation of the kinase activity of JAK2,
and thus to constitutive tyrosine phosphorylation
activity, providing hematopoietic cells with a
proliferative and survival advantage.
t(9;12)(p24;p13) acute leukaemias →
JAK2/ETV6
Disease
Myeloid and lymphoid leukemias; only three cases
described to date; one case each: childhood T-ALL, pre
B-ALL, atypical CML.
Prognosis
Unknown.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(1)
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JAK2 (janus kinase 2)
Strehl S
Goerttler PS, Steimle C, März E, Johansson PL, Andreasson
B, Griesshammer M, Gisslinger H, Heimpel H, Pahl HL. The
Jak2V617F mutation, PRV-1 overexpression and EEC
formation define a similar cohort of MPD patients. Blood
2005;Jun 28; 106(8):2862-2864.
Breakpoints
Griesinger F, Hennig H, Hillmer F, Podleschny M, Steffens R,
Pies A, Wormann B, Haase D, Bohlander SK. A BCR-JAK2
fusion gene as the result of a t(9;22)(p24;q11.2) translocation
in a patient with a clinically typical chronic myeloid leukemia.
Genes Chromosomes Cancer 2005;44(3):329-333.
James C, Ugo V, Le Couédic J-P, Staerk J, Delhommeau F,
Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli
A, Villeval JL, Constantinescu SN, Casadevall N,
Vainchenker,W. A unique clonal JAK2 mutation leading to
constitutive signalling causes polycythaemia vera. Nature
2005;434:1144-1148.
Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT,
Verstovsek S, Beran M, Estey E, Kantarjian HM, Issa JP. JAK2
mutation 1849G >T is rare in acute leukemias but can be found
in CMML, Philadelphia-chromosome negative CML and
megakaryocytic leukemia. Blood 2005;Jul 21; [Epub ahead of
print].
References
Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score
J, Seear R, Chase AJ, Grand FH, White H, Zoi C, Loukopoulos
D, Terpos E, Vervessou EC, Schultheis B, Emig M, Ernst T,
Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT,
Reiter A, Cross NC. Widespread occurrence of the JAK2
V617F mutation in chronic myeloproliferative disorders. Blood
2005;106:2162-2168.
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT,
Mauchauffé M, Berthou C, Lessard M, Berger R, Ghysdael J,
Bernard OA. A TEL-JAK2 fusion protein with constitutive
kinase activity in human leukemia. Science 1997;278:13091312.
Peeters P, Raynaud SD, 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 1997;90:2535-2540.
Kralovics R, Passamonti F, Buser AS, Teo S-S, Tiedt R,
Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-offunction mutation of JAK2 in myeloproliferative disorders. New
Eng J Med 2005;352:1779-1790.
Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli
A, Passamonti F, Pietra D, Cazzola M, Skoda RC. Altered
gene expression in myeloproliferative disorders correlates with
activation of signaling by the V617F mutation of Jak2. Blood
2005;Aug 4; [Epub ahead of print].
Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH,
Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria R
Jr, Marynen P, Gilliland DG. Transformation of hematopoietic
cell lines to growth-factor independence and induction of a fatal
myelo- and lymphoproliferative disease in mice by retrovirally
transduced TEL/JAK2 fusion genes. EMBO J 1998;17:53215333.
Lasho TL, Mesa R, Gilliland DG, Tefferi A. Mutation studies in
CD3+, CD19+ and CD34+ cell fractions in myeloproliferative
disorders with homozygous JAK2(V617F) in granulocytes. Br J
Haematol 2005;130:797-799.
Carron C, Cormier F, Janin A, Lacronique V, Giovannini M,
Daniel MT, Bernard O, Ghysdael J. TEL-JAK2 transgenic mice
develop T-cell leukemia. Blood 2000;95:3891-3899.
Levine RL, Loriaux M, Huntly BJ, Loh M, Beran M, Stoffregen
E, Berger R, Clark JJ, Willis SG, Nguyen K, Flores N, Estey E,
Gattermann N, Armstrong S, Look TA, Griffin JD, Bernard OA,
Gilliland DG, Druker BJ, Deininger MW. The JAK2V617F
activating mutation occurs in chronic myelomonocytic leukemia
and acute myeloid leukemia, but not in acute lymphoblastic
leukemia or chronic lymphocytic leukemia. Blood 2005;Aug 4;
[Epub ahead of print].
Ho JM, Nguyen MH, Dierov JK, Badger KM, Beattie BK,
Tartaro P, Haq R, Zanke BW, Carroll MP, Barber DL. TELJAK2 constitutively activates the extracellular signal-regulated
kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK),
and p38 signaling pathways. Blood 2002;100:1438-1448.
Antonioli E, Guglielmelli P, Pancrazzi A, Bogani C, Verrucci M,
Ponziani V, Longo G, Bosi A, Vannucchi AM. Clinical
implications of the JAK2 V617F mutation in essential
thrombocythemia. Leukemia 2005;19(10):1847-1849.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly
BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J,
Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Fröhling S,
Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A,
Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee
SJ, Gilliland DG. Activating mutation in the tyrosine kinase
JAK2 in polycythemia vera, essential thrombocythemia, and
myeloid metaplasia with myelofibrosis. Cancer Cell
2005;7:387-397.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N,
Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott
MA, Erber WN, Green AR: Cancer Genome Project. Acquired
mutation of the tyrosine kinase JAK2 in human
myeloproliferative disorders. Lancet 2005;365:1054-1061.
Bousquet M, Quelen C, De Mas V, Duchayne E, Roquefeuil B,
Delsol G, Laurent G, Dastugue N, Brousset P. The
t(8;9)(p22;p24) translocation in atypical chronic myeloid
leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene
2005;Aug 8; [Epub ahead of print].
Johan MF, Goodeve AC, Bowen DT, Frew ME, Reilly JT. JAK2
V617F Mutation is uncommon in chronic myelomonocytic
leukaemia. Br J Haematol 2005;130:968.
Frohling S, Scholl C, Gilliland DG, Levine RL. Genetics of
myeloid malignancies: pathogenetic and clinical implications. J
Clin Oncol 2005;23:6285-6295.
Murati A, Gelsi-Boyer V, Adélaïde J, Pérot C, Talmant P,
Giraudier S, Lodé L, Letessier A, Delaval B, Brunel V, Imbert
M, Garand R, Xerri L, Birnbaum D, Mozziconacci MJ,
Chaffanet M. PCM1-JAK2 fusion in myeloproliferative
Atlas Genet Cytogenet Oncol Haematol. 2006;10(1)
Mahon FX. JAK the trigger. Oncogene 2005;Jul 4; [Epub
ahead of print].
5
JAK2 (janus kinase 2)
disorders and acute erythroid leukemia
translocation. Leukemia 2005;19(9):1692-1696.
Strehl S
with
t(8;9)
Sulong S, Case M, Minto L, Wilkins B, Hall A, Irving J. The
V617F mutation in Jak2 is not found in childhood acute
lymphoblastic leukaemia. Br J Haematol 2005;130:964-965.
Pesu M, O'shea J, Hennighausen L, Silvennoinen O.
Identification of an acquired mutation in jak2 provides
molecular insights into the pathogenesis of myeloproliferative
disorders. Mol Interv 2005;5:211-215.
Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase
mutation in myeloproliferative disorders: status report and
immediate implications for disease classification and diagnosis.
Mayo Clin Proc 2005;80:947-958. (Review).
Reiter A, Walz C, Watmore A, Schoch C, Blau I,
Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA,
Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, Benedetti
F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A,
Cross NC. The t(8;9)(p22;p24) is a recurrent abnormality in
chronic and acute leukemia that fuses PCM1 to JAK2. Cancer
Res 2005;65:2662-2667.
Tefferi A, Gilliland DG. JAK2 in Myeloproliferative Disorders is
Not Just Another Kinase. Cell Cycle 2005;4(8):1053-1056.
Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, Ito E.
JAK2 Val617Phe activating tyrosine kinase mutation in juvenile
myelomonocytic leukemia. Leukemia 2005;19(10):1843-1844.
Shannon K, Van Etten RA. JAKing up hematopoietic
proliferation. Cancer Cell 2005;7:291-293.
Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ.
Identification of an acquired JAK2 mutation in polycythemia
vera. J Biol Chem 2005;280:22788-22792.
Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure
RF, Levine RL, Gilliland DG, Tefferi A. The JAK2 V617F
activating tyrosine kinase mutation is an infrequent event in
both 'atypical' myeloproliferative disorders and myelodysplastic
syndromes. Blood 2005;106:1207-1209.
This article should be referenced as such:
Strehl S. JAK2 (janus kinase 2). Atlas Genet Cytogenet Oncol
Haematol.2006;10(1):3-6.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(1)
6