BCL6 enables Ph acute lymphoblastic leukemia cells to survive BCR-ABL1 kinase inhibition

Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
Nature (Impact Factor: 42.35). 05/2011; 473(7347):384-8. DOI: 10.1038/nature09883
Source: PubMed

ABSTRACT Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL11 and other oncogenic tyrosine kinases2,3. Recent efforts focused on the development of more potent TKI that also inhibit mutant tyrosine kinases4,5. However, even effective TKI typically fail to eradicate leukemia-initiating cells6–8, which often cause recurrence of leukemia after initially successful treatment. Here we report on the discovery of a novel mechanism of drug-resistance, which is based on protective feedback signaling of leukemia cells in response to TKI-treatment. We identified BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukemia-initiating subclones.
BCL6 is a known proto-oncogene that is often translocated in diffuse large B cell lymphoma (DLBCL)9. In response to TKI-treatment, BCR-ABL1 acute lymphoblastic leukemia (ALL) cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in DLBCL (Fig. 1a). Upregulation of BCL6 in response to TKI-treatment represents a novel defense mechanism, which enables leukemia cells to survive TKI-treatment: Previous work suggested that TKI-mediated cell death is largely p53-independent. Here we demonstrate that BCL6 upregulation upon TKI-treatment leads to transcriptional inactivation of the p53 pathway. BCL6-deficient leukemia cells fail to inactivate p53 and are particularly sensitive to TKI-treatment. BCL6−/− leukemia cells are poised to undergo cellular senescence and fail to initiate leukemia in serial transplant recipients. A combination of TKI-treatment and a novel BCL6 peptide inhibitor markedly increased survival of NOD/SCID mice xenografted with patient-derived BCR-ABL1 ALL cells. We propose that dual targeting of oncogenic tyrosine kinases and BCL6-dependent feedback (Supplementary Fig. 1) represents a novel strategy to eradicate drug-resistant and leukemia-initiating subclones in tyrosine kinase-driven leukemia.

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Available from: Yong-Mi Kim, Aug 27, 2015
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    • "through which such leukemias are able to become drug tolerant and resistant (Kaur et al., 2007; Fei et al., 2010a,b; Parameswaran et al., 2010, 2011, 2012; Duy et al., 2011; Park et al., 2011; Feldhahn et al., 2012). However, it is currently unknown whether pre-B ALL cells that develop drug resistance have modified cell surface glycosylation. "
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    • "(D) Proposed model for BCR/ABL regulation of IL-6 expression. In CML cells, BCR/ABL activates Lin28 expression that blocks Let-7 microRNA maturation (Iliopoulos et al., 2009) and/or blocks BCL6 expression (Duy et al., 2011) hence allowing transcription of the IL-6 gene. Inhibition of BCR/ABL activity by TKI treatment reduces Lin28 expression and/or releases BCL6 hence allowing them to blocks IL-6 expression (Yu et al., 2005). "
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    • "PTEN is critical in adult hematopoietic cells, and its deletion leads to transplantable ALL in association with induction of p16 Ink4a and p53 (Yilmaz et al., 2006; Lee et al., 2010). The PI3K–AKT–FOXO pathway is negatively regulated by PTEN, and in the Duy et al. (2011) and Hurtz et al. pathway (Brunet et al., 1999). In Ph + cells, these TFs are normally inactive and localized to the cytoplasm; however , TKI-mediated inhibition of BCR- ABL leads to their activation and cell cycle arrest (Komatsu et al., 2003). "
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