Modulation of NR2F6 and methods and uses thereof

Abstract

The disclosure provides methods of modulating NR2F6 in a cell or animal in need thereof by administering an effective amount of a NR2F6 modulator.

1 . A method of modulating stem cell growth, proliferation and differentiation comprising administering an effective amount of a NR2F6 modulator to a cell or animal in need thereof. 
     
     
         2 . The method of  claim 1 , wherein the NR2F6 modulator comprises a NR2F6 inhibitor. 
     
     
         3 . The method of  claim 2 , for inhibiting self-renewal of stem cells or for inducing terminal differentiation of stem cells. 
     
     
         4 . The method of  claim 3 , wherein the stem cells are cancer stem cells, leukemia stem cells or myelodysplastic stem cells. 
     
     
         5 . The method of  claim 2  for treating or preventing a hematologic condition or the progression of a hematological condition. 
     
     
         6 . The method of  claim 5 , wherein the hematologic condition is acute leukemia, chronic leukemia or myelodysplastic syndrome. 
     
     
         7 . The method of  claim 2  for inducing differentiation of granulocytic, erythroid or megakaryocytic lineages for the treatment of cytopenia. 
     
     
         8 . The method of  claim 2  for reducing the number of progenitor cells for treating conditions associated with leukocytosis. 
     
     
         9 . The method of  claim 2  for potentiating retinoic acid signaling. 
     
     
         10 . The method of  claim 2  for treating disorders characterized by excessive or hyperactive mast cells. 
     
     
         11 . The method of  claim 2 , wherein the NR2F6 inhibitor is an antisense nucleic acid sequence of the gene encoding NR2F6 as shown in SEQ ID NO: 1 or 4 or variants thereof. 
     
     
         12 . The method of  claim 2 , wherein the NR2F6 inhibitor is a blocking antibody that binds the NR2F6 amino acid sequence as shown in SEQ ID NO:2 or SEQ ID NO:3. 
     
     
         13 . The method of  claim 2 , wherein the NR2F6 inhibitor is a shRNA molecule that inhibits expression of NR2F6. 
     
     
         14 . The method of  claim 13 , wherein the shRNA molecule comprises the nucleic acid sequence as shown in SEQ ID NO:5 or 6. 
     
     
         15 . The method of  claim 1 , wherein the NR2F6 modulator comprises a NR2F6 activator. 
     
     
         16 . The method of  claim 15  for stem cell expansion. 
     
     
         17 . The method of  claim 16 , wherein the stem cells are hematopoietic stem cells. 
     
     
         18 . The method of  claim 17 , wherein the stem cells are derived from peripheral blood, bone marrow, umbilical cord blood, embryonic stem cells or menstrual blood. 
     
     
         19 . The method of  claim 16  for bone marrow transplantation or cell therapies. 
     
     
         20 . The method of  claim 15 , for repressing retinoic acid signaling. 
     
     
         21 . The method of  claim 1 , wherein the animal is a mammal. 
     
     
         22 . The method of  claim 21 , wherein the mammal is human. 
     
     
         23 . A pharmaceutical composition comprising a NR2F6 modulator and a pharmaceutically acceptable carrier or diluent. 
     
     
         24 . A method of monitoring a hematological condition comprising:
 a) determining the level of NR2F6 expression in a sample from a subject; and   b) comparing the level of expression of NR2F6 in the sample with a control;   
       wherein an increase in expression of NR2F6 in the sample from the subject as compared to the control is indicative of a hematological condition. 
     
     
         25 . A shRNA molecule comprising the sequence as shown in SEQ ID NO:5 or 6.