Strategy for Leukemia Therapy

Abstract

The chimeric Bcr-Abl oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). In the cytoplasm, the protein transduces a growth signal that is responsible for overexpansion of cells. In the nucleus, the protein induces apoptosis. The invention is a method of treating cancer/killing Bcr-Abl expressing cells by inducing the translocation of Bcr-Abl to the nucleus to activate the apoptotic pathway in cancer cells.

1 . A method for treating leukemia, the method comprising: 
 a) contacting a population of bone marrow cells with an apoptosis-inducing amount of a combination of a kinase inhibitor and a nuclear export inhibitor; and    b) subsequently contacting the population of bone marrow cells with the nuclear export inhibitor not in combination with the kinase inhibitor.    
     
     
         2 . A method according to  claim 1 , wherein the population of bone marrow cells is a mixture comprising leukemic and non-leukemic bone marrow cells, and wherein the kinase inhibitor and the nuclear export inhibitor combination followed by the nuclear export inhibitor not in combination with the kinase inhibitor are contacted in amounts sufficient to induce apoptosis in the leukemic bone marrow cells and not sufficient to induce apoptosis in the non-leukemic bone marrow cells.  
     
     
         3 . A method according to  claim 2 , wherein substantially all of the leukemic bone marrow cells express a Bcr-Abl protein.  
     
     
         4 . A method according to  claim 1 , wherein the kinase inhibitor is capable of inhibiting c-Abl.  
     
     
         5 . A method according to  claim 1 , wherein the kinase inhibitor is selected from the group consisting of STI571, PD173955 and PD180970.  
     
     
         6 . A method according to  claim 1 , wherein the kinase inhibitor is STI571.  
     
     
         7 . A method according to  claim 1 , wherein the nuclear export inhibitor is Leptomycin B.  
     
     
         8 . A method according to  claim 1 , wherein the leukemia is a chronic myologenous leukemia.  
     
     
         9 . A method according to  claim 1 , wherein the population of bone marrow cells is isolated from a mammal.  
     
     
         10 . A method according to  claim 9 , wherein the mammal is a mouse.  
     
     
         11 . A method according to  claim 9 , further comprising: 
 c) administering at least one bone marrow cell to the mammal.    
     
     
         12 . A method according to  claim 9 , further comprising: 
 c) killing substantially all leukemic bone marrow cells comprised by the mammal; and    d) subsequently administering at least one bone marrow cell to the mammal.    
     
     
         13 . A method according to  claim 1 , wherein the population of bone marrow cells is comprised by a mammal.  
     
     
         14 . A method according to  claim 13 , wherein the mammal is a mouse.  
     
     
         15 . A method for selectively inducing apoptosis in leukemic bone marrow cells, wherein the leukemic bone marrow cells are comprised by a mixture of leukemic and non-leukemic bone marrow cells, the method comprising: 
 a) contacting a combination of a kinase inhibitor and a nuclear transport inhibitor with the mixture of leukemic and non-leukemic bone marrow cells; and    b) subsequently contacting the mixture of leukemic and non-leukemic bone marrow cells with the nuclear export inhibitor not in combination with the kinase inhibitor,    wherein the kinase inhibitor and a nuclear transport inhibitor combination followed by the nuclear export inhibitor not in combination with the kinase inhibitor is contacted in an amount sufficient to induce apoptosis in the leukemic bone marrow cells and not sufficient to induce apoptosis in the non-leukemic bone marrow cells.    
     
     
         16 . A method according to  claim 15 , wherein substantially all of the leukemic bone marrow cells comprise a Bcr-Abl protein.  
     
     
         17 . A method according to  claim 15 , wherein the kinase inhibitor is capable of inhibiting c-Abl.  
     
     
         18 . A method according to  claim 15 , wherein the kinase inhibitor is selected from the group consisting of STI571, PD173955 and PD180970.  
     
     
         19 . A method according to  claim 15 , wherein the kinase inhibitor is STI571.  
     
     
         20 . A method according to  claim 15 , wherein the nuclear export inhibitor is Leptomycin B.  
     
     
         21 . A method according to  claim 15 , wherein the mixture of leukemic and non-leukemic bone marrow cells is isolated from a mammal.  
     
     
         22 . A method according to  claim 21 , wherein the mammal is a mouse.  
     
     
         23 . A method according to  claim 15 , wherein the mixture of leukemic and non-leukemic bone marrow cells is comprised by a mammal.  
     
     
         24 . A method according to  claim 23 , wherein the mammal is a mouse.  
     
     
         25 . A method according to  claim 1 , wherein the population of bone marrow cells is a mixture comprising leukemic and non-leukemic bone marrow cells, and wherein the kinase inhibitor and the nuclear export inhibitor combination followed by the nuclear export inhibitor not in combination with the kinase inhibitor are contacted in amounts sufficient to induce apoptosis in the leukemic bone marrow cells and not sufficient to induce apoptosis in the non-leukemic bone marrow cells, and further wherein the kinase inhibitor is STI571 and the nuclear export inhibitor is Leptomycin B.  
     
     
         26 . A method of  claim 25  wherein the leukemic cells comprise CML or ALL.  
     
     
         27 . A method according to  claim 1 , wherein the population of bone marrow cells is a mixture comprising leukemic and non-leukemic bone marrow cells, and wherein the kinase inhibitor and the nuclear export inhibitor combination followed by the nuclear export inhibitor not in combination with the kinase inhibitor are contacted in amounts sufficient to induce apoptosis in the leukemic bone marrow cells and not sufficient to induce apoptosis in the non-leukemic bone marrow cells, and further wherein the kinase inhibitor is PD173955 and PD180970, and the nuclear export inhibitor is Leptomycin B.  
     
     
         28 . A method of  claim 27  wherein the leukemic cells comprise CML or ALL