Synapse - Heterodimeric JAK STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

Heterodimeric JAK STAT activation as a mechanism of persistence to JAK2 inhibitor therapy Journal Article

Authors:	Koppikar, P.; Bhagwat, N.; Kilpivaara, O.; Manshouri, T.; Adli, M.; Hricik, T.; Liu, F.; Saunders, L. M.; Mullally, A.; Abdel-Wahab, O.; Leung, L.; Weinstein, A.; Marubayashi, S.; Goel, A.; Gonen, M.; Estrov, Z.; Ebert, B. L.; Chiosis, G.; Nimer, S. D.; Bernstein, B. E.; Verstovsek, S.; Levine, R. L.
Article Title:	Heterodimeric JAK STAT activation as a mechanism of persistence to JAK2 inhibitor therapy
Abstract:	The identification of somatic activating mutations in JAK2 (refsĝ€‰1ĝ€"4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAKĝ€"STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors. © 2012 Macmillan Publishers Limited. All rights reserved.
Journal Title:	Nature
Volume:	489
Issue:	7414
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2012-09-06
Start Page:	155
End Page:	159
Language:	English
DOI:	10.1038/nature11303
PROVIDER:	scopus
PUBMED:	22820254
PMCID:	PMC3991463
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84865735256&partnerID=40&md5=ab6c6a7c4c79e555324ec560230c06ea
Notes:	--- - "Cited By (since 1996): 2" - "Export Date: 1 October 2012" - "CODEN: NATUA" - "Source: Scopus"