Research Article: JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms

Date Published: February 16, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Mar Bellido, Peter A. W. te Boekhorst.

http://doi.org/10.1155/2012/535709

Abstract

JAK2 is a tyrosine kinase gene that plays an essential role in the development of normal haematopoiesis. Hyperactivation of JAK2 occurs in myeloproliferative neoplasms by different mechanisms. As a consequence, JAK2 inhibitors have been designed to suppress the cytokine signalling cascade caused by the constitutive activation of JAK2. In clinical trials, JAK2 inhibitors are efficient in decreasing spleen size, controlling clinical symptoms, and improving quality of life in patients with myeloproliferative neoplasms. However, JAK2 inhibitors are unable to target uncommitted hematopoietic progenitors responsible of the initiation of the myeloproliferative disease. It is expected that, in order to cure the myeloproliferative disease, JAK2 inhibitors should be combined with other drugs to target simultaneously different pathways and to target the initiator hematopoietic cell population in myeloproliferative disorders. Taking advantage of the inhibition of the cytokine cascade of JAK2 inhibitors, these compounds are going to be used not only to treat patients with hematological neoplasms but may also be beneficial to treat patients with rheumatoid arthritis or other inflammatory diseases.

Partial Text

Myeloproliferative neoplasms (MPNs) are clonal disorders up to now characterized by the autonomous proliferation of committed hematopoietic progenitors secondary to an aberrant activation of tyrosine kinase (TK) signalling pathways in combination with an exaggerated response to hematopoietic cytokines and growth factors [1, 2]. Constitutive activation of TKs is a consistent molecular signature in cell proliferation. Examples of Constitutive activation of TKs are seeing in solid tumours [3, 4], rheumatoid arthritis [5], and hematopoietic malignancies [6]. Known mechanisms of TK activation may result from acquired heterozygote of homozygote point mutations [7, 8], internal tandem duplications [9], and chromosomal translocations [10, 11]. The knowledge of the molecular mechanism involved in the pathogenesis of chronic myeloid leukemia (CML) [12] has allowed to elucidate the molecular dissection of chronic proliferation in MPN. Using CML as paradigm of constitutive activation of TK in chronic myeloproliferation, James et al. sequenced the coding exons and intron-exon junctions of JAK2 in 3 polycythemia vera (PV) patients and 2 controls. In 2 of these patients a G-to-T mutation at nucleotide 1849 in exon 12 was found, leading to a substitution of valine to phenylalanine at position 617 (V617F). This mutation was not a polymorphism, but a recurrent acquired mutation that was found in granulocytes, erythroblasts, and platelets of 40 out of 45 PV patients but not in any controls or patients with secondary erythrocytosis [13]. JAK2V617F was also found in other BCR-ABL negative MPN [14]. JAK2V617F occurs in the pseudokinase domain of the JAK2 gene. The mutated pseudokinase domain is not able to negatively regulate the kinase domain of JAK2, resulting in an autonomous activation of the JAK2 kinase domain with subsequently persistent phosphorylation of STAT and MAPK proteins [15, 16] and hyperstimulation of the cytokine signalling pathway [17]. As a consequence, cells expressing the JAK2V617F mutation are hypersensitive to hematopoietic cytokine stimulation, resulting in an abnormal erythroid-, myeloid-, and thromboproliferation. Moreover, JAK2-deficient mice do not survive because of absence of erythropoiesis. Myeloid progenitors of these mice fail to respond to EPO, GM-CSF, and thrombopoietin stimulation [18]. These experiments demonstrate that JAK2 plays an essential role in the development of normal hematopoiesis.

Hyper-activation of JAK2 is a critical step in the pathogenesis of BCR-ABL1 negative, classical MPN.

JAK2 is a tyrosine kinase gene which plays an essential role in the development of normal haematopoiesis and in the cytokine signalling pathway involving STAT3 and STAT5 proteins. Hyperactivation of JAK2 occurs in MPN by different genetic mechanisms. JAK2 inhibitors have been designed to suppress the cytokine cascade initiated by the activation of JAK2, independently of the underlying genetic mechanism. In phase II/III of clinical trials, JAK2 inhibitors are efficient to control clinical symptoms and to improve quality of life. Recently, it has been demonstrated that JAK2 can also be located in the nucleus of cells, where it plays a role in the transcriptional control of genes regulated by HP1a. Whether JAK2 inhibitors may have a role in the suppression of the nuclear role of JAK2 or not is at the moment unknown, but it opens new insights for the combined use of epigenetic therapy with JAK2 inhibitors for the treatment of MPN.

 

Source:

http://doi.org/10.1155/2012/535709

 

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