By Lynda Williams, Senior medwireNews Reporter
Nuclear β-catenin could be a treatment target for patients whose chronic myeloid leukaemia (CML) is resistant to tyrosine kinase inhibitors (TKIs) independent of additional BCR–BL1 mutations, US researchers suggest.
“Collectively, our data implicate nuclear β-catenin in intrinsic BCR-ABL1 kinase-independent TKI resistance, but argue against a direct role for β-catenin in BM [bone marrow]-mediated (extrinsic) TKI resistance”, write Michael Deininger, from the University of Utah in Salt Lake City, and co-investigators.
However, writing in Leukemia, they add “the caveat that even primary CML cells cultured ex vivo on primary MSCs [mesenchymal stromal cells] may not fully recapitulate persistent leukemia cells in patients on long-term imatinib therapy, including heterogeneity across patients.”
The team demonstrated that imatinib therapy reduced β-catenin levels in TKI-sensitive cell lines but had no impact on β-catenin in cells lines with either intrinsic or extrinsic BCR-ABL1 kinase-independent TKI resistance, indicating that “imatinib-resistant cells have uncoupled β-catenin expression from BCR-ABL1 activity.”
Short hairpin RNA-mediated β-catenin knockdown reduced proliferation and increased apoptosis in CML cell lines with intrinsic BCR-ABL1 kinase-independent TKI resistance, with a more pronounced effect in the presence of imatinib. Cells taken from patients with clinical TKI resistance and wild-type BCR-ABL1 also had reduced ability to proliferate when treated with the β-catenin knockdown.
When in direct contact with BM stromal cells, β-catenin protein levels were “fully restored” in cells with β-catenin knockdown, as was colony formation suggesting that the stromal cells stabilise β-catenin protein, in a calcium-dependent manner, and may play a role in imatinib resistance.
But Lef/Tcf reporter assay activity in CML cells, designed to detect endogenous β-catenin transcription, did not increase in the presence of imatinib or BM stromal cells or MSCs, nor did β-catenin target gene expression alter.
β-catenin connects cadherins involved in cell to cell communication to the cell cytoskeleton, the researchers explain. β-catenin stabilisation did not alter N-cadherin-or H-cadherin-mediated extrinsic resistance to imatinib, which the authors say adds support to the hypothesis that β-catenin stabilisation and nuclear β-catenin activation “are not required in extrinsic TKI resistance, or that such an effect is highly dependent on the stromal line used.”
Demonstrating for the first time that H-cadherin has multiple effects on CML cells grown in BM stroma, including downregulation of β-catenin activity in the nucleus and survival in the presence of imatinib, the team concludes: “Our data suggest that targeting H-cadherin may be therapeutically useful, but more experimentation will be required to dissect its diverse functions on leukemic and normal hematopoietic progenitor cells.”
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