JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are a group of disorders defined by clonal proliferation of mature myeloid cells with overlapping clinical features. The driver mutations of these disorders, namely JAK2 (Janus Kinase), MPL (Myeloproliferative Leukaemia Virus) and CALR (Calreticulin) upregulate JAK...

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Bibliographic Details
Published in:Molecular and cellular endocrinology 2017-08, Vol.451, p.71-79
Main Authors: O'Sullivan, Jennifer M., Harrison, Claire N.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - therapeutic use
Calreticulin - genetics
Calreticulin - metabolism
Cell Proliferation - drug effects
Cell Survival - drug effects
Gene Expression Regulation, Neoplastic
Hematologic Neoplasms - drug therapy
Hematologic Neoplasms - genetics
Hematologic Neoplasms - metabolism
Hematologic Neoplasms - pathology
Humans
JAK inhibitor
JAK-STAT
Janus Kinase 2 - genetics
Janus Kinase 2 - metabolism
Molecular Targeted Therapy
Myeloid Cells - drug effects
Myeloid Cells - metabolism
Myeloid Cells - pathology
Myeloproliferative Disorders - drug therapy
Myeloproliferative Disorders - genetics
Myeloproliferative Disorders - metabolism
Myeloproliferative Disorders - pathology
Myeloproliferative neoplasm
Primary myelofibrosis
Pyrazoles - therapeutic use
Receptors, Thrombopoietin - genetics
Receptors, Thrombopoietin - metabolism
Ruxolitinib
Signal Transduction
STAT Transcription Factors - genetics
STAT Transcription Factors - metabolism
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Summary:Myeloproliferative neoplasms (MPN) are a group of disorders defined by clonal proliferation of mature myeloid cells with overlapping clinical features. The driver mutations of these disorders, namely JAK2 (Janus Kinase), MPL (Myeloproliferative Leukaemia Virus) and CALR (Calreticulin) upregulate JAK-STAT signaling with increase in downstream transcription and gene expression. Epigenetic mutations are prevalent in MPNs but their interplay with aberrant JAK-STAT signaling is not known. This understanding lead to development of first targeted treatment in MPN; ruxolitinib for primary myelofibrosis. This has shown clinical benefit in overall survival and symptoms improvement but has yet to show significant disease modifying effects. This review will focus on contemporaneous understanding of altered JAK-STAT signaling in MPN and targeted treatments in clinical practice.
ISSN:0303-7207
1872-8057
DOI:10.1016/j.mce.2017.01.050