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: 41.46). 05/2011; 473(7347):384-8. DOI: 10.1038/nature09883
Source: PubMed


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.

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Available from: Yong-Mi Kim,
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    • "In contrast, in stem cells, BCR-ABL-dependent Akt pathway activation is repressed by TGF-beta signaling, which limits oncogenic stress [72]. Bcl-6 – as a downstream target of FoxO3 has also been demonstrated to bind to and repress Arf and p53 promoters in BCR-ABL-positive ALL [74] and in CML [73•], which also compromises the p53 checkpoint (Fig. 1). Finally, reduced p53 function was shown to result from BCR-ABL-induced overexpression of the deacetylase SIRT1, which selectively increases survival of CML stem cells [59, 75]. "
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    ABSTRACT: Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction.
    Current Hematologic Malignancy Reports 02/2014; 9(1). DOI:10.1007/s11899-013-0196-8 · 2.20 Impact Factor
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    • "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 [48]. "
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    ABSTRACT: BCR-ABL tyrosine kinase inhibitors (TKIs) are effective in controlling Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) are unlikely to cure the disease because TKIs are unable to eradicate leukemia stem cells (LSCs) responsible for the disease relapse even after tyrosine kinase inhibition. In addition, the TKI resistance of LSCs is not associated with the BCR-ABL kinase domain mutations. These observations indicate that TKI-insensitive LSCs and TKI-sensitive leukemic progenitor cells are biologically different, which leads us to believe that LSCs and more differentiated leukemic cells have different genetic mechanisms. Further study of LSCs to identify the novel gene signatures and mechanisms that control the function and molecular phenotype of LSCs is critical. In this mini-review, we will discuss our current understanding of the biology of LSCs and novel genes that could serve as a molecular signature of LSCs in CML. These novel genes could also serve as potential targets for eradicating LSCs in CML.
    06/2013; 1(1). DOI:10.1186/2050-7771-1-21
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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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    ABSTRACT: The development of resistance to chemotherapy is a major cause of relapse in acute lymphoblastic leukemia (ALL). Though several mechanisms associated with drug resistance have been studied in detail, the role of carbohydrate modification remains unexplored. Here, we investigated the contribution of 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) to survival and drug resistance development in ALL cells. A strong induction of 9-O-acetylated Neu5Ac including 9-O-acetyl GD3 was detected in ALL cells that developed resistance against vincristine or nilotinib, drugs with distinct cytotoxic mechanisms. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to such drugs. Moreover, removal of intracellular and cell surface-resident 9-O-acetyl Neu5Ac by lentiviral transduction of the esterase was lethal to ALL cells in vitro even in the presence of stromal protection. Interestingly, expression of the esterase in normal fibroblasts or endothelial cells had no effect on their survival. Transplanted mice induced for expression of the O-acetylesterase in the ALL cells exhibited a reduction of leukemia to minimal cell numbers and significantly increased survival. This demonstrates that Neu5Ac 9-O-acetylation is essential for survival of these cells and suggests that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells.
    Journal of Experimental Medicine 03/2013; 210(4). DOI:10.1084/jem.20121482 · 12.52 Impact Factor
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