Ikaros and CK2 regulate expression of Bcl-xL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia
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PROVIDER: PRJNA593992 | ENA |
REPOSITORIES: ENA
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Project description:High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the Ikaros tumor suppressor. In leukemia, Ikaros’ function is impaired by oncogenic Casein Kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces Ikaros binding to the promoter of its target gene, particularly Bcl-xL. This results in a loss of Ikaros-mediated repression of Bcl-xL and in increased expression of Bcl-xL. Increased expression of Bcl-xL and/or CK2, as well as reduced Ikaros expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, enhances Ikaros-mediated repression of Bcl-xL and increases sensitivity to doxorubicin. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia and lays the groundwork for clinical testing of CK2 inhibitors in combination with doxorubicin for the treatment of hematopoietic malignancies.
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Project description:Bcl-xL is an anti-apoptotic protein that is frequently found to be overexpressed in non-small cell lung cancer leading to an inhibition of apoptosis and poor prognosis. Recently, the role of miRNAs in regulating apoptosis and cell survival during tumorigenesis has become evident, with cancer cells showing perturbed expression of various miRNAs. We utilized miRNA microarrays to determine if miRNA dysregulation in bcl-xL silenced lung adenocarcinoma cells could be involved in regulating apoptotic behavior, and identified dysregulated miRNAs with putative targets involved in signal transduction pathways regulating apoptosis, cell proliferation and cell progression. Short interfering RNA-based transfection of A549 was carried out inducing a reduction in bcl-xL expression levels. 24 hours post-transfection total RNA was isolated using TRIzol reagent and hybridized onto Affymetrix GeneChip miRNA Arrays. A global miRNA expression profile was then established, which compared total RNA, extracted from siRNA-transfected and non-transfected A549 cells. All experiments were carried out with three independent biological replicates.
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Project description:Genome-wide genetic screens have identified cellular dependencies in many cancers. Using Novartis’ DRIVE and the Broad Institute’s Achilles shRNA screening datasets, we mined for targetable dependencies in kidney lineage cancer cells. Our studies identified a dependency, preferentially in kidney cancer cells versus cells of other lineages, on the BCL2L1 gene, which encodes the Bcl-xL anti-apoptotic protein. Genetic and pharmacological inactivation of Bcl-xL, but not its paralog BCL2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Expression levels of Bcl-xL, VHL status, and p53 mutation status were insufficient to predict Bcl-xL dependence. Instead, analyzing the transcriptional hallmarks of response to Bcl-xL blockade identified an elevated mesenchymal cell state signature in Bcl-xL dependent lines. Functional studies to address if these cell state differences drive Bcl-xL dependence showed that maintaining mesenchymal characteristics was necessary to confer sensitivity to Bcl-xL loss; and, conversely, that promoting mesenchymal transition was sufficient to increase sensitivity to Bcl-xL inhibition in resistant cells. This mesenchymal signature was also observed in almost a third of human renal tumors, and is associated with worse clinical outcomes. Detachment from an organized epithelium incites protective apoptotic responses in normal cells (e.g. anoikis); however, our findings suggest that, in mesenchymal kidney cancer cells Bcl-xL activity counteracts this protective mechanism and enables tumor cell survival. Altogether, our studies uncover an unexpected link between cellular cell state and dependence on anti-apoptotic proteins, and justify the use of Bcl-xL blockade to target a clinically aggressive subset of human kidney cancers.
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Project description:Bcl-xL is an anti-apoptotic protein that is frequently found to be overexpressed in non-small cell lung cancer leading to an inhibition of apoptosis and poor prognosis. Recently, the role of miRNAs in regulating apoptosis and cell survival during tumorigenesis has become evident, with cancer cells showing perturbed expression of various miRNAs. We utilized miRNA microarrays to determine if miRNA dysregulation in bcl-xL silenced lung adenocarcinoma cells could be involved in regulating apoptotic behavior, and identified dysregulated miRNAs with putative targets involved in signal transduction pathways regulating apoptosis, cell proliferation and cell progression.
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Project description:Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determined crystal structures of VHL/753b/BCL-xL and VHL/753b/ BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/PZ753b-linker/target interfaces. The importance of these interfacial contacts was validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This resulted in the design of a novel degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we were able to explain the enhanced target degradation of BCL-2/BCL-xL in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.
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