Ikaros isoforms and mutants

Abstract

Specific Ikaros mutations, as well as the correlation of the presence of the specific Ikaros mutations and other wild-type non-DNA binding Ikaros isoforms with lymphoid cell abnormality is provided in the in the invention. Methods for detecting and treating lymphoid cell abnormality, including hematologic malignancy, are also provided.

We claim:  
     
         1 . A nucleic acid sequence encoding at least a portion of an Ikaros protein and comprising the sequence of one or more of SEQ ID NO: 24, SEQ ID NO: 25; SEQ ID NO: 10, and SEQ ID NO: 26.  
     
     
         2 . An Ikaros peptide produced by expression of the nucleic acid sequence of  claim 1 .  
     
     
         3 . A method for the detection of abnormal lymphohematopoietic cells, comprising analyzing a sample of lymphoid cells for the presence of aberrantly spliced Ikaros isoforms.  
     
     
         4 . The method of  claim 3 , comprising analyzing said cells for Ikaros isoforms having a molecular weight of less than about 47 kDa.  
     
     
         5 . The method of  claim 3 , comprising analyzing said cells for Ikaros isoforms encoded at least in part by exons 6-7 and lacking the following Ikaros amino acid sequence: KSSMPQKFLG.  
     
     
         6 . The method of  claim 3 , comprising analyzing said cells for Ikaros isoforms having an insertion of the following amino acid sequence: VTVGADDFRDFHAIIPKSFSR.  
     
     
         7 . The method of  claim 3 , wherein said lymphohematopoietic cells are malignant cells.  
     
     
         8 . The method of  claim 3 , wherein said analyzing is by Western blot detection, and wherein an abundance of small isoforms, less than about 42 kDa, is diagnostic of lymphohematopoietic cell abnormality.  
     
     
         9 . The method of  claim 3 , wherein said analyzing is by confocal light microscopy, and wherein a diffuse, cytoplasmic localization of Ikaros protein is diagnostic of lymphohematopoietic cell abnormality.  
     
     
         10 . The method of  claim 3 , wherein said cells are analyzed for expression of Ikaros isoforms, and wherein an abundance of dominant negative isoforms is diagnostic of lymphohematopoietic cell abnormality.  
     
     
         11 . The method of  claim 10 , wherein expression of Ikaros isoforms Ik-4, Ik-6, Ik-7, Ik-8, or a combination thereof, is correlated with lymphohematopoietic cell abnormality.  
     
     
         12 . The method of  claim 3 , wherein said analyzing comprises amplification of Ikaros coding sequences.  
     
     
         13 . The method of  claim 3 , wherein said analyzing comprises immunoreaction with anti-Ikaros antibodies.  
     
     
         14 . The method of  claim 3 , wherein said abnormality is leukemia or lymphoma.  
     
     
         15 . A method for the detection of hematologic malignancy, the method comprising: analyzing a sample of hematologic cells for expression of Ikaros protein isoforms; and correlating the expression of dominant negative Ikaros isoforms with hematologic malignancy.  
     
     
         16 . The method of  claim 15 , wherein said malignancy is lymphoma.  
     
     
         17 . The method of  claim 15 , wherein said malignancy is non-Hodgkin's lymphoma.  
     
     
         18 . The method of  claim 15 , wherein said malignancy is Hodgkin's lymphoma.  
     
     
         19 . The method of  claim 15 , wherein said malignancy is selected from common ALL, T-ALL, infant-ALL, or AML.  
     
     
         20 . A method for the treatment of hematologic malignancy, said method comprising expressing in hematologic cells an increased amount of Ik-1 or Ik-2, said expression increased as compared with a non-treated control.  
     
     
         21 . A method for the diagnosis of cancer cells, comprising analyzing a cell sample for expression of non-DNA binding Ikaros protein isoforms; and correlating the expression of non-DNA binding Ikaros isoforms with hematologic malignancy.  
     
     
         22 . (New) A method of treating a hematological cell having a lymphoid disease characterized by a reduced amount of Ikaros-1, Ikaros-2, Ikaros-3, or some combination thereof in the hematological cell as compared with a normal hematological cell comprising administering Ikaros-1, Ikaros-2, Ikaros-3, or some combination thereof to the hematological cell.  
     
     
         23 . (New) The method of  claim 22 , wherein the lymphoid disease involves T-cells or B-cells.  
     
     
         24 . (New) The method of  claim 22 , wherein the lymphoid disease is stem cell leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, or secondary leukemia.  
     
     
         25 . The method of  claim 22 , wherein said step of administering comprises administering Ikaros-1, Ikaros-2, or some combination thereof.