Mutations in the bcr-abl tyrosine kinase associated with resistance to sti-571

Abstract

The invention described herein relates to novel genes and their encoded proteins, termed Mutants Associated with Resistance to STI-571 (e.g., T315I Bcr-Abl), and to diagnostic and therapeutic methods and compositions useful in the management of various cancers that express MARS. The invention further provides methods for identifying molecules that bind to and/or modulate the functional activity of MARS.

1 - 50 . (canceled) 
     
     
         51 . A method of detecting an imatinib-resistant mutant abl kinase domain in a Bcr-Abl polypeptide in an individual, the method comprising the steps of:
 a) obtaining a sample containing DNA or RNA coding for a Bcr-Abl polypeptide, or obtaining a sample containing a Bcr-Abl polypeptide, from the individual;   b) determining the nucleotide sequence of the codon in the DNA or RNA that codes for the amino acid residue at the position corresponding to amino acid position 255 of SEQ ID NO: 1, or determining the amino acid residue of the polypeptide at the position corresponding to amino acid position 255 of SEQ ID NO: 1; and   c) comparing the amino acid residue at amino acid position 255 of SEQ ID NO: 1 with the amino acid residue coded for by the codon, or with the amino acid residue of the polypeptide, a E to K mutation indicating that the individual has a Bcr-Abl polypeptide having an imatinib-resistant mutant abl kinase domain.   
     
     
         52 . The method of  claim 51 , wherein the step of determining the nucleotide sequence of the codon in the DNA or RNA comprises sequencing. 
     
     
         53 . The method of  claim 51 , wherein the step of determining the nucleotide sequence of the codon in the DNA or RNA comprises using a nucleic acid amplification assay selected from the group consisting of branched DNA and TMA. 
     
     
         54 . The method of  claim 51 , wherein the amino acid residue of the polypeptide is determined using an immunoassay. 
     
     
         55 . A method of detecting an imatinib-resistant mutant abl kinase domain in a Bcr-Abl polypeptide in an individual, the method comprising the steps of:
 a) obtaining a sample containing DNA or RNA coding for a Bcr-Abl polypeptide, or obtaining a sample containing a Bcr-Abl polypeptide, from the individual;   b) determining the nucleotide sequence of the codon in the DNA or RNA that codes for the amino acid residue at the position corresponding to amino acid position 255 of SEQ ID NO: 1, or determining the amino acid residue of the polypeptide at the position corresponding to amino acid position 255 of SEQ ID NO: 1; and   c) comparing the amino acid residue at amino acid position 255 of SEQ ID NO: 1 with the amino acid residue coded for by the codon, or with the amino acid residue of the polypeptide, a E to V mutation indicating that the individual has a Bcr-Abl polypeptide having an imatinib-resistant mutant abl kinase domain.   
     
     
         56 . The method of  claim 55 , wherein the step of determining the nucleotide sequence of the codon in the DNA or RNA comprises sequencing. 
     
     
         57 . The method of  claim 55 , wherein the step of determining the nucleotide sequence of the codon in the DNA or RNA comprises using a nucleic acid amplification assay selected from the group consisting of branched DNA and TMA. 
     
     
         58 . The method of  claim 55 , wherein the amino acid residue of the polypeptide is determined using an immunoassay.