Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies

Cosgun, K. N.; Jumaa, H.; Robinson, M. E.; Liang, X.; Xiao, G.; Chan, L. N.; Lee, J.; Kume, K.; Leveille, E.; Fonseca-Arce, D.; Khanduja, D.; Ng, H. L.; Feldhahn, N.; Song, J.; Chan, W. C.; Chen, J.; Taketo, M. M.; Kothari, S.; Davids, M. S.; Schjerven, H.; Jellusova, J.; Mueschen, M.

doi:10.1101/2023.03.13.532152

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bioRxiv · 10.1101/2023.03.13.532152

Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies

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Abstract

In most cell types, nuclear {beta}-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of {beta}-catenin but critically depended on GSK3{beta} for effective {beta}-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that {beta}-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, {beta}-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive {beta}-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3{beta} small molecule inhibitors to subvert {beta}-catenin degradation. Clinically approved GSK3{beta}-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of {beta}-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3{beta}-inhibitors for targeted engagement of lymphoid-specific {beta}-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTSO_LIUnlike other cell lineages, B-cells express nuclear {beta}-catenin protein at low baseline levels and depend on GSK3{beta} for its degradation. C_LIO_LIIn B-cells, {beta}-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. C_LIO_LICRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed {beta}-catenin-dependent Myc repression and induction of cell death. C_LIO_LIThe discovery of GSK3{beta}-dependent degradation of {beta}-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3{beta}-inhibitors for the treatment of refractory B-cell malignancies. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/532152v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1b70e4dorg.highwire.dtl.DTLVardef@10bfcc8org.highwire.dtl.DTLVardef@b10eorg.highwire.dtl.DTLVardef@1683a3e_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIAbundant nuclear {beta}-catenin C_LIO_LI{beta}-catenin pairs with TCF7 factors for transcriptional activation of MYC C_LIO_LIB-cells rely on efficient degradation of {beta}-catenin by GSK3{beta} C_LIO_LIB-cell-specific expression of Ikaros factors C_LI Unique vulnerability in B-cell tumors: O_LIGSK3{beta}-inhibitors induce nuclear accumulation of {beta}-catenin. C_LIO_LI{beta}-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC C_LI

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Cosgun, K. N., Jumaa, H., Robinson, M. E., Liang, X., Xiao, G., Chan, L. N., Lee, J., Kume, K., Leveille, E., Fonseca-Arce, D., Khanduja, D., Ng, H. L., Feldhahn, N., Song, J., Chan, W. C., Chen, J., Taketo, M. M., Kothari, S., Davids, M. S., Schjerven, H., Jellusova, J., Mueschen, M.. 2023-03-15. Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies. https://doi.org/10.1101/2023.03.13.532152

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