BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Philadelphia cromosome-positive leukemia

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Publication Type honors thesis
School or College College of Science
Department Biology
Faculty Mentor Thomas O'Hare
Creator Estrada, Johanna
Title BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Philadelphia cromosome-positive leukemia
Year graduated 2014
Date 2014-04
Description CML 1s caused by a random reciprocal translocation that joins the ABL1 gene on chromosome 9, with the BCR gene on chromosome 22. The result is the formation of the oncogenic BCR-ABL1 gene. This derivative chromosome is widely known as the Philadelphia Chromosome (Ph+), and it encodes a deregulated, constitutively activated tyrosine kinase called BCR-ABL1. Ponatinib is the only approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 point mutant-based resistance in Philadelphia chromosome-positive (Ph+) leukemia, including the highly resistant BCRABL1T3151 mutant. However, the development of compound mutants (2 mutations in the same BCR-ABL1 molecule) may inhibit ponatinib binding, and lead to treatment failure. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib and bosutinib. T315I-inclusive compound mutants confer high-level TKI resistance, including to ponatinib. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants present different levels of TKI resistance, requiring rational treatment selection to optimize clinical outcome.
Type Text
Publisher University of Utah
Subject Leukemia -- Genetic aspects -- Research Leukemia -- Treatment -- Research
Language eng
Rights Management Copyright © Johanna Estrada 2014
Format Medium application/pdf
Format Extent 685,054 bytes
Identifier etd3/id/3564
Permissions Reference URL https://collections.lib.utah.edu/ark:/87278/s6dn7zhr
ARK ark:/87278/s65m9dz6
Setname ir_htoa
Date Created 2015-07-21
Date Modified 2019-07-11
ID 197116
Reference URL https://collections.lib.utah.edu/ark:/87278/s65m9dz6
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