Research Publications


Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors.

Waibel, M; Solomon, VS; Knight, DA; Ralli, RA; Kim, SK; Banks, KM; Vidacs, E; Virely, C; Sia, KC; Bracken, LS; Collins-Underwood, R; Drenberg, C; Ramsey, LB; Meyer, SC; Takiguchi, M; Dickins, RA; Levine, R; Ghysdael, J; Dawson, MA; Lock, RB; Mullighan, CG; Johnstone, RW
Cell reports
Journal Article; Research Support, Non-U.S. Gov't
To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.
Molecular Medicine
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

Creation Date 2014-02-21 08:58:54