vendredi 2 septembre 2011

Mutated genes in cancer (11) – JAK2


In databases:

● Entrez ( 3717 or JAK2
● Ensembl ( ENSG00000096968
● UniProt ( O60674
● GeneCards ( JAK2
● HGNC ( 6192 or JAK2
● Enzyme Number (IUBMB): EC 2.7.10, EC

Gene locus:


Protein name:

Janus kinase 2

Protein Size:

1132 amino acids; about 131 kDa


Janus tyrosine kinase 2 (Jak2), the protein coded by JAK2, is a protein tyrosine kinase of the non-receptor type that associates with the intracellular domains of various receptors.  It plays pivotal functions for signal transduction from hematopoietic cytokine (IL-3, GM-CSF, erythropoietin) receptors, mediating the activation of STAT proteins, required in definitive erythropoiesis (mice that do not express an active protein for this gene exhibit embryonic lethality). It is also involved in growth hormone (GH) induced activation of the GH receptor. It has been found to be constitutively associated with the prolactin receptor.

Cancer-related alterations:

Four translocations involving JAK2 have been described to date:

            t(5;9)(q14.1;p24.1)     SSBP2-JAK2      ● Pre-B-ALL
            t(8;9)(p22;p24)           PCM1-JAK2       ● Atypical CML, CEL, ALL, NHL
            t(9;12)(p24;p13)         JAK2-ETV6        ● T-ALL, B-ALL, CML
            t(9;22)(p24;q11.2)      JAK2-BCR         ● CML

B-ALL: B-cell acute lymphocytic leukaemia; T-ALL: T-cell acute lymphocytic leukemia; CML: chronic myeloid leukemia; CEL: chronic eosinophilic leukemia; NHL: non-Hodgkin lymphoma.

Somatic JAK2 mutations are seen in about 40% of hematopoietic and lymphoid tissue tumors. A high proportion (> 50%) of patients with myeloproliferative disorders (MPD) (polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis - see below) carry a dominant gain-of-function 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 (characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly), from 41-57% in patients with essential thrombocythemia (characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications), and from 23-95% in patients with idiopathic myelofibrosis (characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension). 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 "Philadelphia Chromosome negative" (Ph-negative) atypical CML, in more than 10% of chronic myelomonocytic leukemia (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 hematopoietic malignancies of the myeloid lineage.


Both JAK-2 (TG101348) and JAK-1/2 (INCB018424, CYT387) inhibitors are currently in development.

References (open access):

The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues. Van Etten RA, Koschmieder S, Delhommeau F, Perrotti D, Holyoake T, Pardanani A, Mesa R, Green T, Ibrahim AR, Mughal T, Gale RP, Goldman J. Haematologica. 2011 Apr;96(4):590-601.

Therapeutic potential of JAK2 inhibitors. Verstovsek S. Hematology Am Soc Hematol Educ Program. 2009:636-42.

Myeloproliferative neoplasms: From JAK2 mutations discovery to JAK2 inhibitor therapies. Passamonti F, Maffioli M, Caramazza D, Cazzola M. Oncotarget. 2011 Jun;2(6):485-90.

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