JAK2 clinical mutations cause myeloproliferative neoplasms and leukemia, and the mutations strongly concentrate in the regulatory pseudokinase domain Janus kinase homology (JH) 2.
While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation.
Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections.
In approximately 60% of patients, the Janus kinase 2 gene is mutated, in 20%, the calreticulin gene is mutated, and in 5%, the myeloproliferative leukemia virus gene is mutated.
Having both a tyrosine kinase-activating rearrangement and genomic lesions affecting lymphoid transcription factors suggested that the leukemia was of the Philadelphia chromosome (Ph)/BCR-ABL1-like ALL subtype and that JAK2 inhibitors might be able to overcome this aggressive ALL with SPAG9-JAK2.
SHP1 negatively regulates the Janus kinase 2/signal transducer and activator of transcription (JAK2/STAT) signaling pathway, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia.
Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling has an important role in the oncogenesis of myeloproliferative neoplasms (MPNs) and leukemia.
We previously showed that CD34⁺/CD38⁻ acute myelogenous leukemia (AML) cells, which contain leukemia stem cells, expressed a greater amount of the phosphorylated forms of JAK2 and STAT5 (p-JAK2 and p-STAT5) than their CD34⁺/CD38⁺ counterparts.
This study was conducted to investigate whether any association exists between genetic polymorphisms in the JAK2, STAT3 and STAT5 genes and individual susceptibility to leukemia.
Among the patients with myelofibrosis, those with ASXL1 lesions were not distinguished from their wild-type counterparts with regard to JAK2V617F status, exposure to chemotherapy or evolution to leukemia.
Mutations in the thrombopoietin receptor gene (myeloproliferative leukemia, MPL) have been reported in patients with JAK2V617F-negative chronic myeloproliferative disorders (MPDs).
To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients.
Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma.
Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3epsilon- and pTalpha-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCRalphabeta transgene that mimics pre-TCR signaling.
Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice.
We conclude that all human TEL/JAK2 fusion variants are oncoproteins in vitro that strongly activate STAT 5, and cause lethal myelo- and lymphoproliferative syndromes in murine bone marrow transplant models of leukemia.