Beta-catenin shows treatment target potential for TKI-resistant CML

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.”

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News-Medical.Net.
Post a new comment
Post
You might also like... ×
Dangerous brain parasite invades host cell, maintains steady nutrient supply