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.
In particular, gain-of-function mutations in the <i>JAK</i> genes, most frequently, V617F in the pseudokinase domain of JAK2, have been mapped in patients with blood disorders, including myeloproliferative neoplasms and leukemias.
JAK2 clinical mutations cause myeloproliferative neoplasms and leukemia, and the mutations strongly concentrate in the regulatory pseudokinase domain Janus kinase homology (JH) 2.
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.
Mutations in the thrombopoietin receptor gene (myeloproliferative leukemia, MPL) have been reported in patients with JAK2V617F-negative chronic myeloproliferative disorders (MPDs).
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.
Tauhese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia.
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.
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.
Continued research into how miRNAs impact JAK2(V617F) clonal expansion, differential haematopoiesis among different MPNs, disease progression and leukaemia transformation will lead to a better understanding of the development of these disorders, their clinical manifestations, and their treatment.
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.
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.
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.
A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS, and TET2, without significant differences between JAK2-mutant and wild-type leukemias.