Acute Myelogenous Leukemia Biomarkers

Abstract

The present invention provides novel compositions and their use in classifying acute myelogenous leukemia.

1 . A composition comprising an AML biomarker, wherein the AML biomarker consists of between 2 and 60 different probe sets, wherein at least 20% of the different probe sets comprise one or more isolated polynucleotides that selectively hybridize to a genomic region selected from the group consisting of 11p15.2; 5q11.2; 2q32.2; 7p11.2; 15q21.1; 11p15.5; 10p14; 15q26.2; 1q22; 10q26.11; 8p11.21; and 9q32; wherein the different probe sets in total selectively hybridize to at least two of the recited genomic regions. 
     
     
         2 . The composition of  claim 1  wherein the different probe sets in total selectively hybridize to at least three of the recited genomic regions. 
     
     
         3 . The composition of  claim 1  wherein at least 50% of the different probe sets comprise one or more isolated polynucleotides that selectively hybridize to one of the recited genomic regions. 
     
     
         4 . The composition of  claim 1  wherein the different probe sets in total selectively hybridize to at least genomic regions 11p15.5, 8p11.21, and 9q32. 
     
     
         5 . A composition comprising an AML biomarker consisting of between 2 and 65 different probe sets, wherein at least 20% of the different probe sets comprise one or more isolated polynucleotides that selectively hybridize to a nucleic acid according to formula 1, or complements thereof:
   X1−X2−X3;   wherein X2 is a human genomic insert contained within a bacterial artificial chromosome (“BAC”) selected from the group consisting of SEQ ID NOS:14-41, wherein X1 and X3 are independently 0-500 kB of human genomic nucleic acid flanking X2 in the human genome; and   wherein the different polynucleotide probe sets in total selectively hybridize to at least two non-overlapping polynucleotides according to formula 1, or complements thereof.   
     
     
         6 . The composition of  claim 5  wherein the different probe sets in total selectively hybridize to at least three non-overlapping polynucleotides according to formula 1, or complements thereof. 
     
     
         7 . The composition of  claim 5  wherein at least 50% of the different probe sets comprise one or more isolated polynucleotides that selectively hybridize to a nucleic acid according to formula 1, or complements thereof. 
     
     
         8 . The composition of  claim 5 , wherein the different probe sets in total selectively hybridize to at least three different nucleic acids according to Formula I having X2 groups as follows:
 a) one or more of SEQ ID NO:26-27, or complements thereof;   b) one or more of SEQ ID NO:40-41, or complements thereof; and   c) SEQ ID NO: 39, or complements thereof.   
     
     
         9 . A composition comprising an AML biomarker consisting of between 2 and 65 different probe sets, wherein at least 20% of the different probe sets comprise one or more isolated polynucleotides that selectively hybridize to a nucleic acid sequence according to one of SEQ ID NOS:1-13 or complements thereof; wherein the different probe sets in total selectively hybridize to at least two of the recited nucleic acid sequences according to SEQ ID NOS:1-13 or complements thereof. 
     
     
         10 . The composition of  claim 9  wherein the different probe sets in total selectively hybridize to at least three of the recited nucleic acid sequences according to SEQ ID NOS:1-13 or complements thereof. 
     
     
         11 . The composition of  claim 9  wherein at least 50% of the different probe sets comprise one or more isolated polynucleotides that selectively hybridize to a nucleic acid sequence according to one of SEQ ID NOS:1-13 or complements thereof. 
     
     
         12 . The composition of  claim 9 , wherein the different probe sets in total selectively hybridize to at least SEQ ID NO:6, SEQ ID NO:12, and SEQ ID NO:13. 
     
     
         13 . A method for classifying AML in a patient, comprising
 (a) contacting a nucleic acid sample obtained from a subject having AML with polynucleotide probes that, in total, selectively hybridize to two or more genomic regions selected from the group consisting of 11p15.2; 5q11.2; 2q32.2; 7p11.2; 15q21.1; 11p15.5; 10p14; 15q26.2; 1q22; 10q26.11; 8p11.21; and 9q32; wherein the contacting occurs under conditions to promote selective hybridization of the polynucleotides of the probe set to the two or more genomic regions;   (b) detecting formation of hybridization complexes;   (c) determining whether one or more of the genomic regions are present in an altered copy number in the nucleic acid sample; and   (d) correlating an altered copy number of one or more of the genomic regions with an AML classification.   
     
     
         14 . The method of  claim 13 , further comprising identifying the AML patient as being of a normal karyotype subclass prior to or simultaneously with carrying out steps (a)-(d). 
     
     
         15 . The method of  claim 13 , further comprising determining an AML morphological subtype in the patient. 
     
     
         16 . The method of  claim 13 , wherein a decrease in copy number of the one or more genomic regions is correlated with an increased risk of recurrence of AML. 
     
     
         17 . The method of  claim 13 , wherein a decrease in copy number of the one or more genomic regions is correlated with a higher risk of poor outcome, selected from the group consisting of relapse, death due to disease, shorter disease-free survival, and shorter event-free survival. 
     
     
         18 . The method of  claim 17 , further comprising determining a course of treatment for the AML patient. 
     
     
         19 . The method of  claim 13  wherein the polynucleotide probes consist of the composition of  claim 1 . 
     
     
         20 . The method of  claim 13  wherein the polynucleotide probes consist of the composition of  claim 5 . 
     
     
         21 . A method for classifying AML comprising:
 (a) contacting a mRNA-derived nucleic acid sample obtained from a subject having AML with nucleic acid probes that, in total, selectively hybridize to two or more nucleic acid targets selected from the group consisting of SEQ ID NO:1-13 or complements thereof; wherein the contacting occurs under conditions to promote selective hybridization of the nucleic acid probes to the nucleic acid targets, or complements thereof, present in the nucleic acid sample;   (b) detecting formation of hybridization complexes between the nucleic acid probes to the nucleic acid targets, or complements thereof, wherein a number of such hybridization complexes provides a measure of gene expression of the one or more nucleic acids according to SEQ ID NO:1-13; and   (c) correlating an alteration in gene expression of the one or more nucleic acids according to SEQ ID NO:1-13 relative to control with an AML classification.   
     
     
         22 . The method of claim  121 , further comprising identifying the AML patient as being of a normal karyotype subclass prior to or simultaneously with carrying out steps (a)-(c). 
     
     
         23 . The method of  claim 21 , further comprising determining an AML morphological subtype in the patient. 
     
     
         24 . The method of  claim 21 , wherein a decrease in gene expression of the one or more nucleic acids according to SEQ ID NO:1-13 relative to control with an AML classification is correlated with an increased risk of recurrence of AML. 
     
     
         25 . The method of  claim 21 , wherein a decrease in gene expression of the one or more nucleic acids according to SEQ ID NO:1-13 relative to control with an AML classification is correlated with a higher risk of poor outcome, selected from the group consisting of relapse, death due to disease, shorter disease-free survival, and shorter event-free survival. 
     
     
         26 . The method of  claim 25 , further comprising determining a course of treatment for the AML patient. 
     
     
         27 . The method of  claim 21  wherein the polynucleotide probes consist of the composition of  claim 9 . 
     
     
         28 . The method of  claim 21  wherein the polynucleotide probes consist of the composition of  claim 12 . 
     
     
         29 . A kit comprising the composition of  claim 1  and a set of instructions for using the composition for AML classification. 
     
     
         30 . The kit of  claim 29  wherein the polynucleotides are detectably labeled. 
     
     
         31 . The kit of  claim 30 , wherein the detectable labels on the different probe sets are distinguishable from each other