Natural-killer/t-cell lymphoma (nktcl) susceptibility prediction, diagnosis and therapy

Abstract

Natural-Killer T-Cell Lymphoma (NKTCL) susceptibility prediction, diagnosis and therapy. The invention relates to a method for predicting Natural Killer T-cell Lymphoma (NKTCL) susceptibility and/or diagnosing NKTCL in a subject comprising testing for JAK mutations. The invention also relates to a method of screening for candidate agents capable of treating NKTCL using a cell line comprising at least one JAK mutation. The invention includes an NKTCL animal model comprising at least one JAK mutation. The invention also includes JAK inhibitors for treating NKTCL.

1 . A method for predicting Natural Killer T-Cell Lymphoma (NKTCL) susceptibility and/or diagnosing NKTCL in a subject, comprising testing for the genotype of said subject for at least one JAK gene or testing for whether said subject expresses a wildtype or mutant JAK protein, wherein the presence of a mutant JAK gene indicates that a subject is at risk of developing and/or has NKTCL. 
     
     
         2 . The method according to  claim 1 , wherein:
 when the method comprises testing for the genotype of said subject for at least one JAK gene, the method comprises testing for the genotype of said subject for at least one of JAK1, JAK2, JAK3 and/or TYK2 genes; and   when the method comprises testing for whether said subject expresses a wildtype or mutant JAK protein, the method comprises testing for whether said subject expresses wildtype and/or at least one mutant JAK1, JAK2, JAK3 and/or TYK2 protein.   
     
     
         3 . (canceled) 
     
     
         4 . The method according to  claim 1 , wherein:
 a wildtype JAK3 gene comprises SEQ ID NO: 1 and the mutant JAK3 gene comprises a substitution of C with T at nucleotide 15792 and/or a substitution of C with T at nucleotide 15795 of SEQ ID NO: 1; and/or   a wildtype JAK1 gene comprises SEQ ID NO: 3 and the mutant gene comprises a substitution of T with G at nucleotide 124823 of SEQ ID NO:3.   
     
     
         5 . (canceled) 
     
     
         6 . The method according to  claim 1 , further comprising providing an isolated blood and/or cell sample from the subject for said testing. 
     
     
         7 . The method according to  claim 6 , wherein
 when the method comprises testing for the genotype of said subject for at least one JAK gene, the method further comprises isolating nucleic acid molecules from the subject for said testing; and   when the method comprises testing for whether said subject expresses a wildtype or mutant JAK protein, the method further comprises isolating at least one protein from the subject for said testing.   
     
     
         8 . (canceled) 
     
     
         9 . The method according to  claim 1 , wherein when the method comprises testing for the genotype of said subject for at least one JAK gene,
 said testing is performed on genomic DNA, mRNA and/or cDNA; and/or   said testing comprises sequence analysis, restriction fragment length polymorphism analysis, hybridization, polymerase chain reaction (PCR), or reverse transcription PCR   
     
     
         10 - 17 . (canceled) 
     
     
         18 . The method according to  claim 1 , wherein when the method comprises testing for whether said subject expresses a wildtype or mutant JAK protein, the testing comprises protein sequencing and antibody detection methods. 
     
     
         19 . A method for screening for an agent capable of treating NKTCL, or for an agent capable of reducing the activity of at least one JAK protein,
 the method comprising:   (i) providing a NKTCL cell line comprising at least one mutant JAK gene;   (ii) contacting the NKTCL cell line with the agent; and   (iii) determining the effect of the agent on the mammalian NKTCL cell line;   wherein the ability of the agent to reduce the viability, growth and/or multiplication and/or increase apoptosis of the NKTCL cell line is indicative of the ability of the agent to treat NKTCL, or to reduce the activity of at least one JAK protein.   
     
     
         20 . (canceled) 
     
     
         21 . The method according to  claim 19 , wherein the NKTCL cell line carries at least one of mutant JAK1, JAK2, JAK3 and/or TYK2 genes. 
     
     
         22 . (canceled) 
     
     
         23 . The method according to  claim 19 , wherein the NKTCL cell line carries at least one of the following JAK mutations:
 (i) a substitution of C with Tat nucleotide 15792 of SEQ ID NO: 1;   (ii) a substitution of C with Tat nucleotide 15795 of SEQ ID NO: 1; and   (iii) a substitution of T with G at nucleotide 124823 of SEQ ID NO: 3.   
     
     
         24 . An NKTCL animal model comprising at least one mutant JAK gene. 
     
     
         25 . The NKTCL animal model according to  claim 24 , comprising at least one of mutant JAK1, JAK2, JAK3 and/or TYK2 genes. 
     
     
         26 . (canceled) 
     
     
         27 . The NKTCL animal model according to  claim 24 , comprising at least one of the following mutations:
 (i) a substitution of C with Tat nucleotide 15792 of SEQ ID NO: 1;   (ii) a substitution of C with Tat nucleotide 15795 of SEQ ID NO: 1; or   (iii) a substitution of T with G at nucleotide 124823 of SEQ ID NO: 3.   
     
     
         28 . A method of treating Natural Killer T-Cell Lymphoma (NKTCL) comprising administering at least one JAK inhibitor to a subject. 
     
     
         29 . The method according to  claim 28 , wherein the JAK inhibitor inhibits at least one of JAK1, JAK2, JAK3 and/or TYK2 proteins. 
     
     
         30 - 32 . (canceled) 
     
     
         33 . The method according to  claim 28 , wherein the JAK inhibitor comprises 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile (CP-690,550) and/or (E)-2-cyano-3-(4-nitrophenyl)-N-((R)-1-phenylethyl)acrylamide (WP-1034). 
     
     
         34 - 35 . (canceled) 
     
     
         36 . The method according to  claim 28 , wherein the subject comprises a mammal. 
     
     
         37 . (canceled) 
     
     
         38 . The method according to  claim 28 , wherein the subject with at least one mutation selected from the group consisting of JAK3-A572V, JAK3-A573V and/or JAK1-Y652D. 
     
     
         39 - 56 . (canceled) 
     
     
         57 . The method according to  claim 1 , wherein:
 the wildtype JAK3 protein comprises SEQ ID NO:2 and the mutant JAK3 protein comprises a substitution of A with V at amino acid 572 and/or a substitution of A with V at amino acid 573 of SEQ ID NO:2; and/or   the wildtype JAK1 protein comprises SEQ ID NO: 4 and the mutant JAK1 protein comprises a substitution of Y with D at amino acid 652 of SEQ ID NO:4.