Behavioural deterioration induced by intrahippocampal NAC61–95 injections and attenuation with ibuprofen

Pre-aggregated non-amyloid component of α-synuclein, NAC61–95, was injected bilaterally into the CA3 area of rat hippocampus and behaviour was assessed using an alternating-lever cyclic-ratio (ALCR) schedule of operant responding. Four groups of rats were used (n = 6 per group), subgroups were treated orally with either ibuprofen (40 mg/kg) or vehicle (10% sucrose) twice daily. Intrahippocampal injection of NAC61–95 increased lever switching errors and numbers of activated astrocytes, and ibuprofen treatment alleviated these effect

BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition

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