Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression

Abstract

Transgenic animals containing a nucleic acid sequence encoding TCL1 operably linked to transcriptional control sequences directing expression to B cells are described. Such transgenic animals provide a useful animal model system for human B cell chronic lymphocytic leukemia.

What is claimed:  
     
         1 . A transgenic animal whose genome comprises: a nucleic acid construct comprising at least one transcriptional regulatory sequence capable of directing expression to B cells operably linked to a nucleic acid sequence encoding TCL1.  
     
     
         2 . The transgenic animal of  claim 1  wherein said at least one transcriptional regulatory sequence comprises a V H  promoter.  
     
     
         3 . The transgenic animal of  claim 2  wherein said at least one transcriptional regulatory sequence further comprises a IG H -μ enhancer.  
     
     
         4 . The transgenic animal of  claim 1  wherein said nucleic acid sequence encoding TCL1 comprises a DNA sequence encoding human TCL1.  
     
     
         5 . The transgenic animal of  claim 2  wherein said V H  promoter is derived from mouse.  
     
     
         6 . The transgenic animal of  claim 3  wherein said IG H -μ enhancer is derived from mouse.  
     
     
         7 . The transgenic animal of  claim 1  wherein said animal is a mouse.  
     
     
         8 . The transgenic animal of  claim 1  wherein said animal exhibits an expanded population of CD5+ B cells.  
     
     
         9 . The transgenic animal of  claim 1  wherein said animal exhibits a lymphoproliferative condition.  
     
     
         10 . The transgenic animal of  claim 9  wherein said lymphoproliferative condition comprises a preleukemic state.  
     
     
         11 . The transgenic animal of  claim 9  wherein said lymphoproliferative condition comprises leukemia.  
     
     
         12 . The transgenic animal of  claim 11  wherein said leukemia exhibits characteristics of human B-CLL.  
     
     
         13 . A transgenic animal whose genome comprises a nucleic acid construct comprising a nucleic acid sequence encoding TCL1, wherein said sequence is operably linked to a V H  promoter and to a IG H -μ enhancer, wherein TCL1 is expressed in immature and mature B cells of said animal.  
     
     
         14 . A method of producing animals having a lymphoproliferative disorder comprising the steps of: 
 a) Obtaining white blood cells from a transgenic animal whose genome comprises: a nucleic acid construct comprising at least one transcriptional regulatory sequence capable of directing expression to B cells operably linked to a nucleic acid sequence encoding TCL1;    b) Counting said cells; and    c) Injecting a number of said cells into a recipient animal syngeneic with said transgenic animal, wherein the number of said cells so injected is effective to produce a lymphoproliferative disorder in said recipient animal.    
     
     
         15 . A method of determining the ability of a therapeutic modality to affect a lymphoproliferative disorder, said method comprising the steps of: 
 a) Providing a first transgenic animal whose genome comprises: a nucleic acid construct comprising at least one transcriptional regulatory sequence capable of directing expression to B cells operably linked to a nucleic acid sequence encoding TCL1;    b) Administering said therapeutic modality to said first transgenic animal;    c) Performing an analysis of the population of B cells in said transgenic animal;    d) Providing a control animal, wherein said control animal is a second transgenic animal whose genome comprises: a nucleic acid construct comprising at least one transcriptional regulatory sequence capable of directing expression to B cells operably linked to a nucleic acid sequence encoding TCL1, wherein said control animal does not receive the therapeutic modality;    e) Performing an analysis of the population of B cells in said control animal; and    f) Comparing the analysis of step c) with the analysis of step e), wherein the ability of the therapeutic modality to affect a lymphoproliferative disorder is evidenced by a difference in the B cell population between said first transgenic animal and said control animal.    
     
     
         16 . The method of  claim 15  wherein said lymphoproliferative disorder comprises a B cell neoplasia.  
     
     
         17 . The method of  claim 16  wherein said B cell neoplasia is B-CLL.  
     
     
         18 . The method of  claim 15  wherein said first transgenic animal and said control animal are mice.  
     
     
         19 . The method of  claim 18  wherein said analysis comprises a measurement of the number and/or relative proportion of CD5+ B cells.