BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition
19.05.2011
Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, Klemm L, Kweon SM, Nahar R, Braig M, Park E, Kim YM, Hofmann WK, Herzog S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A, Müschen M.
Nature. 2011;473(7347):384-8.
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR–ABL1 and other oncogenic tyrosine kinases2,3. Recent efforts have focused on developing more
potent TKIs that also inhibit mutant tyrosine kinases4,5. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs)6–8, 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 drugresistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.
