Method Of Inducing Apoptosis In Lymphoid Cells

Abstract

A two-stage, transcriptionally regulated apoptotic program has been discovered. In the first stage, IL-3 withdrawal results in transcriptional activation of the NGAL gene followed by synthesis and secretion of NGAL protein. In the second stage, secreted NGAL protein induces apoptosis in lymphoid cells by an autocrine mechanism. Based on this discovery, the invention provides a method of inducing apoptosis in a lymphoid cell in a mammal, e.g., a human patient. The invention includes administering a therapeutically effective amount of an NGAL polypeptide or NGAL-like polypeptide to a mammal.

1 . A method of inducing apoptosis in a lymphoid cell, the method comprising administering an amount of an NGAL polypeptide effective to induce apoptosis in the lymphoid cell. 
     
     
         2 . The method of  claim 1 , wherein the lymphoid cell is a mammalian cell. 
     
     
         3 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence having at least 80% sequence identity with any one of SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7. 
     
     
         4 . The method of  claim 1 , wherein the polypeptide is a composite sequence alignable with amino acid 21 to the C-terminal amino acid of the NGAL amino acid alignment in  FIG. 9 , wherein each position in the composite sequence contains an amino acid selected from a corresponding position in SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3. 
     
     
         5 . The method of  claim 1 , wherein the polypeptide comprises SEQ ID NO:4, wherein the blank or grey positions in SEQ ID NO:4 contain an amino acid selected from a corresponding position in SEQ ID NO:1 or SEQ ID NO:2. 
     
     
         6 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7 
     
     
         7 . The method of  claim 1 , wherein the lymphoid cell is a cell in vivo. 
     
     
         8 . The method of  claim 1 , wherein the lymphoid cell is a T-lymphocyte or a B-lymphocyte. 
     
     
         9 . The method of  claim 8 , wherein the T-lymphocyte or a B-lymphocyte is leukemic. 
     
     
         10 . The method of  claim 7 , wherein the polypeptide is administered parenterally. 
     
     
         11 . The method of  claim 7 , wherein the polypeptide is administered intravenously. 
     
     
         12 . The method of  claim 7 , wherein the cell is in a human. 
     
     
         13 . A method of treating a leukemia in a mammal, the method comprising administering to the mammal an amount of an NGAL polypeptide effective to ameliorate a. symptom of the leukemia. 
     
     
         14 . The method of  claim 13 , wherein the polypeptide comprises an amino acid sequence having at least 80% sequence identity with any one of SEQ ID NO:5; SEQ ID NO:6; or SEQ ID NO:7. 
     
     
         15 . The method of  claim 13 , wherein the polypeptide is a composite sequence alignable with amino acid 21 to the C-terminal amino acid of the NGAL amino acid alignment in  FIG. 9 , wherein each position in the composite sequence contains an amino acid selected from a corresponding position in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3. 
     
     
         16 . The method of  claim 13 , wherein the polypeptide comprises SEQ ID NO:4, wherein the blank or grey positions in SEQ ID NO:4 contain an amino acid selected from a corresponding position in SEQ ID NO:1 or SEQ ID NO:2. 
     
     
         17 . The method of  claim 13 , wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7. 
     
     
         18 . The method of  claim 13 , wherein the polypeptide is administered parenterally. 
     
     
         19 . The method of  claim 13 , wherein the polypeptide is administered intravenously. 
     
     
         20 . The method of  claim 13 , wherein the mammal is a human. 
     
     
         21 . A method of treating an immune disorder in a mammal, the method comprising administering to the mammal an amount of an NGAL polypeptide effective to reduce a symptom of the immune disorder in the mammal.