A role of JAK in the pathogenesis of Philadelphia negative myeloproliferative neoplasms. Target therapy possibilities

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A role of JAK in the pathogenesis of Philadelphia negative myeloproliferative neoplasms. Target therapy possibilities

Journal Title: OncoReview - Year 2011, Vol 1, Issue 3

Abstract

In recent years a significant progress has been made in understanding of the pathogenesis of myeloproliferative neoplasms, especially the one with mutation in JAK2 gene. In 2005 several study groups confirmed the presence of V617F mutation in exon 14 of JAK2 gene. It was documented that anomaly is present in 96% of polycythaemia vera patients (PV), in 35–70% of patients with essential thrombocythaemia (ET ) and in about 50% of patients with idiopathic myelofibrosis (IMF). Later on, also other sequence aberrations of JAK2 gene were found in exon 12–15, among others a single nucleotide substitutions, insertions or deletions, and also insertion-deletions defects. In the case of most of the mentioned mutations, experimental studies confirmed their relations with abnormal autoinhibition process of JAK 2 and cytokine-independent proliferation of cells carrying defect. Discovery of relation between the presence of mutations in JAK2 gene gave insight to initiation of works to prepare small molecules with inhibitory activity against JAK 2. Initially, non-ATP competitive JAK 2 inhibitors for the APT -binding catalytic site were tested. Thereafter, ATP -competitive pyridones and pyrimidine analogs were independently evaluated. Most of JAK 2 inhibitors belong to ATP competitive inhibitors [TG101348 (Targe- Gen), INCB018424 (ruxolitinib, Incyte), CYT 387 (Cytopia), CEP -701 (lestaurtinib, Cephalon), XL019 (Exelixis), SB1518 (S*Bio, according to Onyx licence as ONX0803) and AZD1480 (AstraZeneca)]. Its administration in myelofibrosis leads to reduction of spleen volume in about 50% of patients, reduction of general symptoms intensity, increase of physical exercise tolerability and improvement of quality-of-life. In PV and ET patients JAK 2 inhibitors therapy resulted in significant improvement of complete blood count results and in significant reduction of flebotomy needs. Presently, most of JAK 2 inhibitors are evaluated in clinical trials. However, it seems that their use may change current standards of therapy of JAK2 positive myeloproliferative neoplasms in the nearest future.

Authors and Affiliations

Krzysztof Lewandowski

Keywords

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