Identification of rnai targets and use of rnai for rational therapy of chemotherapy-resistant leukemia and other cancers

Abstract

Provided is a mosaic mouse model for use in determining the potency of an shRNA in vivo for reducing survival of cancer cells of chemotherapy-resistant leukemia. The syngeneic mouse recipient is transplanted with tet-on competent leukemia cells carrying a bicistronic nucleic acid construct comprising a promoter operably linked to a fusion gene associated with chemotherapy-resistant leukemia, and a sequence encoding a reverse tet-transactivator protein, such that both coding sequences are co-expressed from the promoter. Also provided are methods of treating soft tissue cancers.

1 - 29 . (canceled) 
     
     
         30 . A method for treating chemotherapeutic-resistant acute myeloid leukemia in a subject in need thereof, wherein the subject exhibits a known genotype associated with a chemotherapy-resistant leukemia, the method comprising: administering to the subject a HDAC3 inhibitor, wherein HDAC3 expression is necessary for survival of the chemotherapy-resistant acute myeloid leukemia cell with said known genotype and is dispensable for the growth of non-transformed hematopoietic cells, so as to inhibit survival of acute myeloid leukemia cells in the subject, and thereby treat the chemotherapeutic-resistant acute myeloid leukemia in the subject. 
     
     
         31 . The method of  claim 30 , wherein the known genotype comprises a chromosomal rearrangement resulting in a MLL fusion protein, or AML1/ETO fusion protein. 
     
     
         32 . The method of  claim 31 , wherein the MLL or AML fusion protein is selected from the group consisting of MLL/ENL, MLL/AF9, AML1/ETO9a. 
     
     
         33 . The method of  claim 30 , wherein the HDAC3 inhibitor is a hydroxamate. 
     
     
         34 . The method of  claim 30 , wherein the HDAC3 inhibitor is suberanilohydroxamic acid (SAHA). 
     
     
         35 . A method for treating chemotherapeutic-resistant acute myeloid leukemia in a subject in need thereof, wherein the subject exhibits a known genotype associated with a chemotherapy-resistant leukemia, the method comprising: administering to the subject SAHA, wherein SAHA inhibits HDAC3 and HDAC3 expression is necessary for survival of the chemotherapy-resistant acute myeloid leukemia cell with said known genotype and is dispensable for the growth of non-transformed hematopoietic cells, so as to inhibit survival of acute myeloid leukemia cells in the subject, and thereby treat the chemotherapeutic-resistant acute myeloid leukemia in the subject.