Genetic resistance to JAK 2 enzymatic inhibitors is overcome by HSP 90 inhibition

The Rockefeller University Press $30.00 J. Exp. Med. Vol. 209 No. 2 259-273 www.jem.org/cgi/doi/10.1084/jem.20111694 259 Janus kinase 2 (JAK2) is an intracellular tyrosine kinase that associates with the cytoplasmic do­ mains of multiple cytokine receptors. Ligand binding by the receptor results in conformational changes that activate JAK2, resulting in phospho­ rylation of target proteins, including STATs and JAK2 itself (Ihle and Gilliland, 2007). More than 50% of myeloproliferative neoplasms (MPNs) harbor the activating JAK2 V617F mutation (Levine et al., 2005, 2007). In addition, a subset of B cell acute lymphoblastic leukemia (B­ALL) with rearrangements of cytokine receptor–like factor 2 (CRLF2) have activating JAK2 mutations that primarily involve R683 (Mullighan et al., 2009a; Russell et al., 2009; Hertzberg et al., 2010; Yoda et al., 2010). Additional cases of CRLF2­ rearranged B­ALL lack JAK2 mutations but harbor a CRLF2 F232C or IL7R mutation (Yoda et al., 2010; Shochat et al., 2011) that promotes constitutive receptor dimerization and signaling through wild­type JAK2, which is analogous to the MPL W515L mutation observed in a subset of MPNs (Pikman et al., 2006). CORRESPONDENCE David M. Weinstock: dweinstock@partners.org OR Thomas Radimerski: thomas.radimerski@novartis.com

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