Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia

Area of Science:

• Hematology
• Oncology
• Cell Biology

Background:

• Therapy resistance in chronic myeloid leukemia (CML) is a significant clinical challenge.
• Mutations in the BCR-ABL1 oncogene, particularly BCR-ABL1^T315I, confer resistance to tyrosine kinase inhibitors (TKIs) and are associated with aggressive disease.
• Understanding the mechanisms underlying TKI resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the differences in niche interactions between BCR-ABL1^T315I+ and BCR-ABL1 CML cells.
• To identify novel therapeutic targets for overcoming TKI resistance in CML.
• To explore the role of the extracellular matrix (ECM) and associated signaling pathways in CML progression and resistance.

Main Methods:

• Utilized retroviral transduction/transplantation models of CML and human cell lines.
• Compared niche location and interactions of imatinib-resistant BCR-ABL1^T315I+ leukemia cells with BCR-ABL1 cells.
• Investigated the involvement of integrin β3, integrin-linked kinase (ILK), and fibronectin deposition.
• Evaluated the therapeutic potential of fibronectin and an ILK inhibitor in xenogeneic and syngeneic murine transplantation models.

Main Results:

• BCR-ABL1^T315I+ leukemia cells exhibit distinct niche localization and interactions compared to BCR-ABL1 cells.
• A pathway involving integrin β3, ILK, and fibronectin mediates these differences.
• Treatment with fibronectin showed a trend towards reduced tumor burden in BCR-ABL1^T315I+ CML models.
• ILK inhibition significantly prolonged survival in mice with BCR-ABL1^T315I+ CML.

Conclusions:

• Interactions with ECM proteins via the integrin β3/ILK pathway differentially influence leukemia progression in BCR-ABL1^T315I+ CML.
• Niche targeting by modulating the ECM represents a potential therapeutic strategy for TKI-resistant CML.
• Targeting the ECM microenvironment offers a promising avenue for improving outcomes in patients with CML resistant to standard therapies.