title: BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition.
abstract: 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.
authors: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors: Cihangir
authors: C
authors: Duy
authors: Christian
authors: C
authors: Hurtz
authors: Seyedmehdi
authors: S
authors: Shojaee
authors: Leandro
authors: L
authors: Cerchietti
authors: Huimin
authors: H
authors: Geng
authors: Srividya
authors: S
authors: Swaminathan
authors: Lars
authors: L
authors: Klemm
authors: Soo-mi
authors: SM
authors: Kweon
authors: Rahul
authors: R
authors: Nahar
authors: Melanie
authors: M
authors: Braig
authors: Eugene
authors: E
authors: Park
authors: Yong-mi
authors: YM
authors: Kim
authors: Wolf-Karsten
authors: WK
authors: Hofmann
authors: Sebastian
authors: S
authors: Herzog
authors: Hassan
authors: H
authors: Jumaa
authors: H Phillip
authors: HP
authors: Koeffler
authors: J Jessica
authors: JJ
authors: Yu
authors: Nora
authors: N
authors: Heisterkamp
authors: Thomas G
authors: TG
authors: Graeber
authors: Hong
authors: H
authors: Wu
authors: B Hilda
authors: BH
authors: Ye
authors: Ari
authors: A
authors: Melnick
authors: Markus
authors: M
authors: Müschen
references: Cancer Res. 2010 Oct 1;70(19):7411-20
references: 20876806
references: Cancer Cell. 2010 Apr 13;17(4):400-11
references: 20385364
references: Genes Dev. 2007 Sep 15;21(18):2283-7
references: 17761812
references: Immunity. 2000 Aug;13(2):199-212
references: 10981963
references: Blood. 2009 Apr 9;113(15):3397-405
references: 18927431
references: Mol Cell. 2009 Oct 23;36(2):326-39
references: 19854140
references: Mol Cell Biol. 2004 Nov;24(22):10058-71
references: 15509806
references: Cancer Cell. 2003 Feb;3(2):173-83
references: 12620411
references: Nature. 2010 Feb 4;463(7281):676-80
references: 20130650
references: Oncogene. 2007 Jan 11;26(2):224-33
references: 16819511
references: Nat Med. 2006 Oct;12(10):1175-80
references: 16998483
references: Science. 2004 Jul 16;305(5682):399-401
references: 15256671
references: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6688-93
references: 16618932
references: Cancer Cell. 2009 Nov 6;16(5):401-12
references: 19878872
references: Cancer Res. 2009 Dec 15;69(24):9337-45
references: 19934315
references: Science. 2008 Nov 28;322(5906):1377-80
references: 19039135
references: J Exp Med. 2010 Jun 7;207(6):1209-21
references: 20498019
references: Nat Med. 2010 Feb;16(2):205-13
references: 20072130
references: Cancer Cell. 2009 Aug 4;16(2):137-48
references: 19647224
references: Nature. 2004 Dec 2;432(7017):635-9
references: 15577913
references: N Engl J Med. 2001 Apr 5;344(14):1038-42
references: 11287973
references: Nature. 2005 Aug 4;436(7051):660-5
references: 16079837
references: Cell. 1997 Nov 28;91(5):649-59
references: 9393858
references: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4519-24
references: 19251651
references: Blood. 2002 Jan 1;99(1):319-25
references: 11756187
references: Proc Natl Acad Sci U S A. 2006 May 9;103(19):7444-9
references: 16651519
references: Cancer Cell. 2007 Sep;12(3):280-92
references: 17785208
references: Cell Cycle. 2004 Sep;3(9):1188-95
references: 15467443
references: Nature. 1996 Feb 15;379(6566):645-8
references: 8628398