Genes associated with progression and response in chronic myeloid leukemia and uses thereof

Abstract

The invention provides molecular markers that are associated with the progression of chronic myeloid leukemia (CML), and methods and computer systems for monitoring the progression of CML in a patient based on measurements of these molecular markers. The present invention also provides CML target genes, and methods and compositions for treating CML patients by modulating the expression or activity of these CML target genes and/or their encoded proteins. The invention also provides genes that are associated with resistance to imatinib mesylate (Gleevec™) treatment in CML patients, and methods and compositions for determining the responsiveness of a CML patient to imatinib mesylate treatment based on measurements of these genes and/or their encoded proteins. The invention also provides methods and compositions for enhancing the effect of Gleevec™ by modulating the expression or activity of these genes and/or their encoded proteins.

What is claimed: 
     
         1 . A computer-implemented method for determining the responsiveness of a chronic myeloid leukemia (CML) patient to imatinib mesylate (IM), comprising:
 (a) classifying, on a computer, a marker profile comprising measurements of a plurality of gene products in a cell sample taken from said patient as an IM-sensitive profile or an IM-resistant profile, wherein said gene products are respectively products of at least five of the genes listed in Table 4;   (b) determining said patient as responsive to IM treatment if said marker profile is classified as an IM-sensitive profile, or determining said patient as resistant to IM treatment if said marker profile is classified as an IM-resistant profile; and   (c) outputting to a user, a user interface device, a monitor, a computer readable storage medium, a local computer, or a computer that is part of a network; or displaying; the determination resulting from step (b).   
     
     
         2 . The method of  claim 1 , wherein the gene products are products consisting of 5, 10, 15, 20, 25, 30, 40, 60, 70, 80, 90, 100, 200, or 228 of the genes listed in Table 4. 
     
     
         3 . The method of  claim 1 , further comprising obtaining said marker profile by a method comprising measuring said plurality of gene products in a cell sample taken from said patient. 
     
     
         4 . The method of  claim 3 , wherein said cell sample is a sample from bone marrow or peripheral blood. 
     
     
         5 . The method of  claim 1 , wherein said classifying is carried out by a method comprising using a progression classifier, wherein said progression classifier receives an input comprising said marker profile and provides an output comprising data indicating whether said marker profile is an IM-sensitive profile or an IM-resistant profile. 
     
     
         6 . The method of  claim 1 , wherein the gene products are selected from the group consisting of at least 5, 6, 7, or 8 of the genes selected from the group consisting of serine threonine kinases CTRL, MAP21K14, CLK3, MAP kinase MKNK2, tyrosine kinase oncogene FYN, TCF7, guanine nucleotide binding proteins GNAZ and GNG11, and MAF. 
     
     
         7 . The method of  claim 1 , wherein each of said gene products is a gene transcript. 
     
     
         8 . The method of  claim 7 , wherein measurement of each said gene transcript is obtained by a method comprising contacting a positionally-addressable microarray with nucleic acids from said cell sample or nucleic acids derived therefrom under hybridization conditions, and detecting the amount of hybridization that occurs, said microarray comprising one or more polynucleotide probes complementary to a hybridizable sequence of each said gene transcript. 
     
     
         9 . The method of  claim 7 , wherein measurement of each said gene transcript is obtained by quantitative reverse transcriptase PCR (qRT-PCR). 
     
     
         10 . The method of  claim 1 , wherein each of said plurality of gene products is a protein. 
     
     
         11 . The method of  claim 1 , wherein said classifying is carried out using a progression classifier, wherein said progression classifier receives an input comprising said marker profile and provides an output comprising data indicating whether said marker profile is a IM resistant profile or an IM responsive profile. 
     
     
         12 . The method of  claim 11 , wherein said step of classifying is carried out by a method comprising (i) comparing said marker profile with an IM resistant template profile and/or an IM responsive template profile, wherein said IM resistant template profile and IM responsive template profile are obtained from a training population comprising IM resistant patients and IM responsive patients, respectively; and (ii) classifying said marker profile as an IM resistant profile if said marker profile has a high similarity to said IM resistant template profile and/or has a low similarity to said IM resistant template profile, or classifying said marker profile as an IM responsive profile if said marker profile has a high similarity to said IM responsive template profile and/or has a low similarity to said IM resistant template profile, wherein a high similarity corresponds to a degree of similarity above a predetermined threshold, and wherein a low similarity corresponds to a degree of similarity no greater than said predetermined threshold. 
     
     
         13 . The method of  claim 11 , wherein said step of classifying is carried out by a method comprising (i) comparing said marker profile with said IM resistant template profile or said IM responsive template profile; and (ii) classifying said marker profile as an IM resistant profile if said marker profile has a high similarity to said IM resistant template profile or has a low similarity to said IM responsive template profile, or classifying said marker profile as an IM responsive profile if said marker profile has a high similarity to said IM responsive template profile or has a low similarity to said IM resistant template profile, wherein a high similarity corresponds to a degree of similarity above a predetermined threshold, and wherein a low similarity corresponds to a degree of similarity no greater than said predetermined threshold. 
     
     
         14 . The method of  claim 12 , wherein said step of classifying is carried out by a method comprising (i) comparing said marker profile with said IM resistant template profile and said IM responsive template profile; and (ii) classifying said marker profile as an IM resistant profile if said marker profile has a higher similarity to said IM resistant template profile than to said IM responsive template profile, or classifying said marker profile as a IM responsive profile if said marker profile has a higher similarity to said IM responsive template profile than to said IM resistant template profile. 
     
     
         15 . The method of  claim 11 , wherein said progression classifier is based on a classification method selected from the group consisting of an artificial neural network, a support vector machine, logic regression, linear or quadratic discriminant analysis, decision trees, principal component analysis, and nearest neighbor classifier analysis.