JAK1-gene

The JAK1 gene is located on chromosome 1p31.3 and encodes a membrane protein of the same name that belongs to a class of protein tyrosine kinases (PTK) (Janus kinases). The encoded kinase (JAK1) phosphorylates STAT proteins (Signal Transducers and Activators of Transcription) and plays a key role in interferon-alpha/beta, interferon-gamma and cytokine signal transduction.

The Janus Kinase/Signal Transducer and Activator of Transcription(JAK/STAT) pathway plays an important oncogenic role in myeloproliferative neoplasms (MPNs) and acute lymphoblastic leukemia (ALL). In normal cells, cytokine-induced activation of the JAK/STAT pathway stimulates proliferation, survival, differentiation and functional activation, resulting in tightly regulated, on-demand blood cell production (Vainchenker W et al. 2013).

The JAK1 gene plays a critical role in the expression of genes that mediate inflammation, epithelial remodeling and metastatic cancer progression. The encoded JAK1 kinase plays a key role in the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammatory response and is a therapeutic target in inflammatory system responses. The activity of this gene is directly inhibited by the protein "Suppressor of Cytokine Signaling 1 -SOCS1-".

JAK1 is highly expressed in lymphoid and myeloid cell lines, especially in granulocytes, but is poorly expressed in megakaryocyte-erythroid progenitors (MEPs) and their progeny compared to JAK2. Gain-of-function mutations lead to proliferation of myeloid cells and not of erythroid cells or platelets.

Activating mutations of JAK1 have been reported primarily in prolymphocytic T-cell leukemia(Bellanger D et al. 2014) and acute lymphoblastic leukemia (Mullighan CG et al. 2009), where they have been shown to lead to a poorer prognosis. Transduction of the V658F, V658L and V658I variants of JAK1 leads to factor-independent cell growth of BaF3 cells, whereas transduction of wild-type JAK1 does not,17 so the mutation is undoubtedly pathogenic.

The increased enzyme activity triggers uncontrolled proliferation of lymphoid progenitor cells. Loss-of-function mutations of JAK1 occur with high frequency in tumors with microsatellite instability and may contribute to tumor immune evasion.

1. Baxter EJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054-1061.
2. Bellanger D et al.(2014) Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. Leukemia 28:417-419.
3. Gordon GM et al.(2010) Transforming JAK1 mutations exhibit differential signalling, FERM domain requirements and growth responses to interferon-γ. Biochem J 432:255-265.
4. James C et al.(2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144-1148.
5. Kralovics R et al.(2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779-1790.
6. Levine RL et al.(2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387-397.
7. Mullighan CG et al.(2009) JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 106:9414-9418.
8. Vainchenker W et al.(2013) JAK/STAT signaling in hematological malignancies. Oncogene 32:2601-2613.