BTK acts as a modulator of the response to imatinib in chronic myeloid leukemia

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Imatinib is a targeted therapy for chronic myeloid leukemia (CML) by inhibiting the BCR::ABL1 kinase.
• Drug resistance to imatinib remains a significant clinical challenge in CML treatment.
• Bruton's tyrosine kinase (BTK), typically linked to B cell malignancies, was found downregulated in an imatinib-resistant CML cell line.

Purpose of the Study:

• To investigate the role of Bruton's tyrosine kinase (BTK) in the development of imatinib resistance in chronic myeloid leukemia (CML).
• To determine the impact of BTK expression levels and a specific BTK variant on CML cell sensitivity to imatinib.

Main Methods:

• Analysis of genome-wide expression and genetic aberrations in an in vitro imatinib-resistant CML cell line.
• Experimental manipulation of BTK levels using BTK inhibition, small interfering RNA (siRNA) knockdown, and BTK overexpression.
• Assessment of CML cell proliferation and imatinib susceptibility under various BTK modulation conditions.

Main Results:

• Downregulation of BTK and a novel BTK variant (p.Glu567Arg) were confirmed in imatinib-resistant CML cells.
• BTK inhibition or knockdown significantly reduced imatinib susceptibility.
• BTK overexpression decreased CML cell proliferation and restored imatinib sensitivity in resistant cells.
• The BTK p.Glu567Arg variant increased cell proliferation and abrogated imatinib sensitivity.

Conclusions:

• BTK plays a critical role in imatinib resistance in CML; its absence promotes resistance, while its presence enhances drug response.
• The BTK p.Glu567Arg variant contributes to imatinib resistance by abrogating drug sensitivity.
• BTK exhibits context-dependent functions, acting as an oncogene in B cell malignancies but as a tumor suppressor in other neoplasms like CML.