In:
Blood Advances, American Society of Hematology, Vol. 4, No. 11 ( 2020-06-9), p. 2439-2450
Abstract:
Pharmacological inhibitors of Bruton tyrosine kinase (BTK) have revolutionized treatment of B-lymphocyte malignancies and show great promise for dampening autoimmunity. The predominant BTK inhibitors tether irreversibly by covalently binding to cysteine 481 in the BTK catalytic domain. Substitution of cysteine 481 for serine (C481S) is the most common mechanism for acquired drug resistance. We generated a novel C481S knock-in mouse model and, using a battery of tests, no overt B-lymphocyte phenotype was found. B lymphocytes from C481S animals were resistant to irreversible, but sensitive to reversible, BTK inhibitors. In contrast, irreversible inhibitors equally impaired T-lymphocyte activation in mice, mimicking the effect of treatment in patients. This demonstrates that T-lymphocyte blockage is independent of BTK. We suggest that the C481S knock-in mouse can serve as a useful tool for the study of BTK-independent effects of irreversible inhibitors, allowing for the identification of novel therapeutic targets and pinpointing potential side effects.
Type of Medium:
Online Resource
ISSN:
2473-9529
,
2473-9537
DOI:
10.1182/bloodadvances.2019001319
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2020
detail.hit.zdb_id:
2876449-3
Permalink