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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. [ABSTRACT FROM AUTHOR]

Fibrin plays important roles in the wound healing processes, including blood clotting and platelet aggregation. Additional activities of fibrin were found in this study, which utilizes human THP-1 cells treated 1,25-(OH)2 vitamin D3 and plasminolytic fragments derived from fibrin. Coated fibrin fragment E on culture plates induced cell adhesions and morphological changes of the THP-1 cells, being resembled to tissue macrophages. Morphological changes of the THP-1 cells were caused by microfilament reorganization. IL-1β production was increased in the THP-1 cells by adherent fibrin fragment E, but not by fibrin fragment D or by fibrinogen fragment E. The elevation of IL-1β production is caused by transcriptional activation. Incubation with cytochalacin D, an actin polymerization inhibitor, prevents both microfilament reorganization and morphological changes, but has no effect on the IL-1β production stimulated by fibrin fragment E. This data suggests that the IL-1β production in the THP-1 cells do not require microfilament reorganization and integrin aggregation. Taken together, these results indicate that fibrin matrix plays an additional role in the stimulation of monocytes for production of IL-1β, morphological changes and cell adhesion, resulting in the facilitation of the wound healing processes. [ABSTRACT FROM AUTHOR]