Diagnosis, prognosis and identification of potential therapeutic targets of multiple myeloma based on gene expression profiling

Abstract

Gene expression profiling is a powerful tool that has varied utility. It enables classification of multiple myeloma into subtypes and identifying genes directly involved in disease pathogenesis and clinical manifestation. The present invention used gene expression profiling in large uniformly treated population of patients with myeloma to identify genes associated with poor prognosis. It also demonstrated that over-expression of CKS1B gene, mainly due to gene amplification that was determined by Fluorescent in-situ hybridization to impart a poor prognosis in multiple myeloma. It is further contemplated that therapeutic strategies that directly target CKS1B or related pathways may represent novel, and more specific means of treating high risk myeloma and may prevent its secondary evolution.

1 .- 20 . (canceled) 
     
     
         21 . A detection method comprising:
 a) obtaining a biological sample containing plasma cells from an individual diagnosed as having monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma;   b) contacting the biological sample with a probe that binds to CKS1B gene, a probe that binds to CCND1 gene, a probe that binds to MAF gene, a probe that binds to MAFB gene, a probe that binds to FGFR3 gene, and a probe that binds to MMSET gene; and   c) detecting via fluorescent in situ hybridization a set of signals from the probes bound to the respective genes CKS1B, CCND1, MAF, MAFB, FGFR3, and MMSET.   
     
     
         22 . The method of  claim 21 , wherein said fluorescent in situ hybridization comprises interphase fluorescent in situ hybridization, metaphase fluorescent in situ hybridization, or both. 
     
     
         23 . The method of  claim 21 , wherein the biological sample is a bone marrow sample. 
     
     
         24 . The method of  claim 21 , further comprising determining the presence of a chromosomal translocation of CCND1 gene, MAF gene, MAFB gene, FGFR3 gene, or MMSET gene. 
     
     
         25 . The method of  claim 21 , further comprising determining the presence of translocation t(11;14)(q13;q32), translocation t(4;14)(p21;q32), translocation t(14;16)(q32;q23), or translocation t(14;20)(q32;q13). 
     
     
         26 . The method of  claim 21 , further comprising contacting the biological sample with a probe that binds to an AHCYL1 gene at chromosome position 1p13 and detecting via fluorescent in situ hybridization a signal from the probe bound to the AHCYL1 gene. 
     
     
         27 . The method of  claim 21 , further comprising detecting via fluorescent in situ hybridization a set of signals from the probes bound to the respective genes CKS1B, CCND1, MAF, MAFB, FGFR3, and MMSET in a control sample. 
     
     
         28 . The method of  claim 27 , wherein the control sample is from a healthy individual. 
     
     
         29 . The method of  claim 21 , wherein the biological sample comprises CD138+ plasma cells. 
     
     
         30 . The method of  claim 21 , wherein the biological sample comprises CD138+ plasma cells isolated from bone marrow. 
     
     
         31 . The method of  claim 30 , wherein the CD138+ plasma cells are isolated from bone marrow by immunomagnetic enrichment. 
     
     
         32 . The method of  claim 21 , further comprising assaying the level of expression of CKS1B gene, CCND1 gene, MAF gene, MAFB gene, FGFR3 gene, and MMSET gene. 
     
     
         33 . The method of  claim 32 , wherein the gene expression levels are assayed by DNA microarray or RT-PCR. 
     
     
         34 . The method of  claim 21 , further comprising contacting the biological sample with a probe that binds to a D13S31/RB1 gene at chromosome position 13q14 and/or a probe that binds to a D13S285 gene at chromosome position 13qte, and detecting via fluorescent in situ hybridization a signal from the probe bound to the D13S31/RB1 gene or the D13S285 gene. 
     
     
         35 . The method of  claim 21 , further comprising assaying the level of expression of one or more genes selected from among GNG10, PNPLA4, KIAA1754, AHCYL1, MCLC, EV15, AD-020, PARG1, CTBS, FUCA1, RFP2, FLJ20489, LTBP1, TRIP13, AIM2, SEL1 SLC19A1, LARS2, OPN3, ASPM, CCT2, UBE21, STK6, FLJ13052, FLJ12525, BIRC5, CKAP1, MGC57827, DKFZp7790175, PFN1, ILF3, IFI16, TBRG4, PAPD1, EIF2C2, MGC4308, ENO1, DSG2, EXOSC4, TAGLN2, RUVBL1, ALDOA, CPSF3, MGC15606, LGALS1, RAD18, SNX5, PSMD4, RAN, KIF14, CBX3, TWPO, DKFZP586L0724, WEE1, ROBO1, TCOF1, YWHAZ, and MPHOSP1 in the biological sample. 
     
     
         36 . The method of  claim 35 , wherein the gene expression levels are assayed by DNA microarray or RT-PCR.