Linked Life Data

12149456

Source:http://linkedlifedata.com/resource/pubmed/id/12149456

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2002-8-7
pubmed:abstractText
The Abl tyrosine kinase inhibitor STI-571 is effective therapy for stable phase chronic myeloid leukemia (CML) patients, but the majority of CML blast-crisis patients that respond to STI-571 relapse because of reactivation of Bcr-Abl signaling. Mutations of Thr-315 in the Abl kinase domain to Ile (T315I) were previously described in STI-571-resistant patients and likely cause resistance from steric interference with drug binding. Here we identify mutations of Tyr-253 in the nucleotide-binding (P) loop of the Abl kinase domain to Phe or His in patients with advanced CML and acquired STI-571 resistance. Bcr-Abl Y253F demonstrated intermediate resistance to STI-571 in vitro and in vivo when compared with Bcr-Abl T315I. The response of Abl proteins to STI-571 was influenced by the regulatory state of the kinase and by tyrosine phosphorylation. The sensitivity of purified c-Abl to STI-571 was increased by a dysregulating mutation (P112L) in the Src homology 3 domain of Abl but decreased by phosphorylation at the regulatory Tyr-393. In contrast, the Y253F mutation dysregulated c-Abl and conferred intrinsic but not absolute resistance to STI-571 that was independent of Tyr-393 phosphorylation. The Abl P-loop is a second target for mutations that confer resistance to STI-571 in advanced CML, and the Y253F mutation may impair the induced-fit interaction of STI-571 with the Abl catalytic domain rather than sterically blocking binding of the drug. Because clinical resistance induced by the Y253F mutation might be overcome by dose escalation of STI-571, molecular genotyping of STI-571-resistant patients may provide information useful for rational therapeutic management.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-10224280, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-10964922, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-10988075, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11036109, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11287972, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11287973, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11423618, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11569495, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11753652, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11832214, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11853795, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-11861307, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-1712111, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-6606682, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-7539119, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-7584069, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-8408645, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-8548747, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-8616716, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-8622867, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-8702653, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-8945479, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-9024657, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-9024658, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-9334312, http://linkedlifedata.com/resource/pubmed/commentcorrection/12149456-9500553
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0027-8424
pubmed:author
pubmed:issnType
Print
pubmed:day
6
pubmed:volume
99
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
10700-5
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop.
pubmed:affiliation
Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't