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Title: Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis

Abstract

Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2];  [2]
  1. (AAS)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGN
OSTI Identifier:
1039450
Resource Type:
Journal Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 147; Journal Issue: (2) ; 10, 2011; Journal ID: ISSN 0092-8674
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; APOPTOSIS; IN VITRO; LEUKEMIA; LEUKEMOGENESIS; MICE; MUTANTS; PHOSPHOTRANSFERASES; SENSITIVITY; TARGETS; TYROSINE

Citation Formats

Grebien, Florian, Hantschel, Oliver, Wojcik, John, Kaupe, Ines, Kovacic, Boris, Wyrzucki, Arkadiusz M., Gish, Gerald D., Cerny-Reiterer, Sabine, Koide, Akiko, Beug, Hartmut, Pawson, Tony, Valent, Peter, Koide, Shohei, Superti-Furga, Giulio, Mount Sinai Hospital), Med U. Vienna), UC), and IMP-CNRS). Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis. United States: N. p., 2012. Web. doi:10.1016/j.cell.2011.08.046.
Grebien, Florian, Hantschel, Oliver, Wojcik, John, Kaupe, Ines, Kovacic, Boris, Wyrzucki, Arkadiusz M., Gish, Gerald D., Cerny-Reiterer, Sabine, Koide, Akiko, Beug, Hartmut, Pawson, Tony, Valent, Peter, Koide, Shohei, Superti-Furga, Giulio, Mount Sinai Hospital), Med U. Vienna), UC), & IMP-CNRS). Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis. United States. doi:10.1016/j.cell.2011.08.046.
Grebien, Florian, Hantschel, Oliver, Wojcik, John, Kaupe, Ines, Kovacic, Boris, Wyrzucki, Arkadiusz M., Gish, Gerald D., Cerny-Reiterer, Sabine, Koide, Akiko, Beug, Hartmut, Pawson, Tony, Valent, Peter, Koide, Shohei, Superti-Furga, Giulio, Mount Sinai Hospital), Med U. Vienna), UC), and IMP-CNRS). Thu . "Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis". United States. doi:10.1016/j.cell.2011.08.046.
@article{osti_1039450,
title = {Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis},
author = {Grebien, Florian and Hantschel, Oliver and Wojcik, John and Kaupe, Ines and Kovacic, Boris and Wyrzucki, Arkadiusz M. and Gish, Gerald D. and Cerny-Reiterer, Sabine and Koide, Akiko and Beug, Hartmut and Pawson, Tony and Valent, Peter and Koide, Shohei and Superti-Furga, Giulio and Mount Sinai Hospital) and Med U. Vienna) and UC) and IMP-CNRS)},
abstractNote = {Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention.},
doi = {10.1016/j.cell.2011.08.046},
journal = {Cell},
issn = {0092-8674},
number = (2) ; 10, 2011,
volume = 147,
place = {United States},
year = {2012},
month = {10}
}