Publication Date:
2011-05-20
Description:
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597744/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597744/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duy, Cihangir -- Hurtz, Christian -- Shojaee, Seyedmehdi -- Cerchietti, Leandro -- Geng, Huimin -- Swaminathan, Srividya -- Klemm, Lars -- Kweon, Soo-mi -- Nahar, Rahul -- Braig, Melanie -- Park, Eugene -- Kim, Yong-mi -- Hofmann, Wolf-Karsten -- Herzog, Sebastian -- Jumaa, Hassan -- Koeffler, H Phillip -- Yu, J Jessica -- Heisterkamp, Nora -- Graeber, Thomas G -- Wu, Hong -- Ye, B Hilda -- Melnick, Ari -- Muschen, Markus -- R01 CA026038/CA/NCI NIH HHS/ -- R01 CA085573/CA/NCI NIH HHS/ -- R01 CA137060/CA/NCI NIH HHS/ -- R01 CA137060-01A1/CA/NCI NIH HHS/ -- R01 CA137060-02/CA/NCI NIH HHS/ -- R01 CA137060-03/CA/NCI NIH HHS/ -- R01 CA137060-04/CA/NCI NIH HHS/ -- R01 CA139032/CA/NCI NIH HHS/ -- R01 CA139032-01/CA/NCI NIH HHS/ -- R01 CA139032-02/CA/NCI NIH HHS/ -- R01 CA139032-03/CA/NCI NIH HHS/ -- R01 CA157644/CA/NCI NIH HHS/ -- R01CA026038/CA/NCI NIH HHS/ -- R01CA085573/CA/NCI NIH HHS/ -- R01CA090321/CA/NCI NIH HHS/ -- R01CA104348/CA/NCI NIH HHS/ -- R01CA137060/CA/NCI NIH HHS/ -- R01CA139032/CA/NCI NIH HHS/ -- R01CA157664/CA/NCI NIH HHS/ -- R21 CA152497/CA/NCI NIH HHS/ -- R21 CA152497-01/CA/NCI NIH HHS/ -- R21 CA152497-02/CA/NCI NIH HHS/ -- R21CA152497/CA/NCI NIH HHS/ -- England -- Nature. 2011 May 19;473(7347):384-8. doi: 10.1038/nature09883.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21593872" target="_blank"〉PubMed〈/a〉
Keywords:
ADP-Ribosylation Factor 1/metabolism
;
Animals
;
Cell Survival/drug effects
;
DNA-Binding Proteins/biosynthesis/deficiency/genetics/*metabolism
;
*Drug Resistance, Neoplasm
;
Fusion Proteins, bcr-abl/*antagonists & inhibitors
;
Gene Expression Regulation, Neoplastic/drug effects
;
Humans
;
Mice
;
Mice, Inbred NOD
;
Mice, SCID
;
Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug
;
therapy/genetics/metabolism/*pathology
;
Protein Kinase Inhibitors/*pharmacology/therapeutic use
;
Transcription, Genetic
;
Tumor Suppressor Protein p53/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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