Use of CDK Inhibitors to Enhance Growth and Self-Renewal of Progenitor Cells

Abstract

Methods for using cyclin-dependent kinase (CDK) inhibitors to enhance growth and self-renewal of progenitor cells, in vitro and in vivo.

1 . (canceled) 
     
     
         2 . A method of treating a subject who has a bone marrow failure syndrome (BMFS) or anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a Cyclin-Dependent Kinase inhibitor (CDKi). 
     
     
         3 . The method of  claim 2 , wherein the CDKi inhibits CDK2. 
     
     
         4 . The method of  claim 2 , wherein the subject has erythroid, myeloid, or megakaryocytic cytopenia; congenital neutropenia; Kostmann syndrome; Diamond-Blackfan anemia; Shwachman-Diamond syndrome; congenital amegakaryocytic thrombocytopenia (CAMT); or thrombocytopenia absent radii (TAR) syndrome. 
     
     
         5 . The method of  claim 2 , wherein the subject has hypoplastic marrow or aplastic marrow; Fanconi anemia; or dyskeratosis congenita. 
     
     
         6 . The method of  claim 2 , wherein the BMFS is an inherited BMFS or acquired BMFS. 
     
     
         7 . The method of  claim 6 , wherein the acquired BMFS is aplastic anemia; anemia that is idiopathic or caused by exposure of toxins, drugs, chemicals, radiation, viral infection, malnutrition, or vitamin deficiencies; or myelodysplastic syndrome (MDS). 
     
     
         8 . A method of treating a subject who has a bone marrow failure syndrome (BMFS) or anemia, the method comprising administering to the subject a therapeutically effective amount of early erythroid progenitor cells produced by:
 i) providing a starting population of cells comprising mononuclear cells from cord blood, peripheral blood, bone marrow or other hematopoietic tissues, and   ii) maintaining the starting population in the presence of a sufficient amount of a Cyclin-Dependent Kinase inhibitor (CDKi) under conditions sufficient for generation and expansion of a desired number of early erythroid progenitor cells.   
     
     
         9 . The method of  claim 8 , wherein the CDKi inhibits CDK2. 
     
     
         10 . The method of  claim 8 , wherein the early erythroid progenitor cells are CFU-e cells. 
     
     
         11 . The method of  claim 8 , wherein the starting population comprises Kit+, or Lin− cells. 
     
     
         12 . The method of  claim 8 , wherein the starting population has been enriched for Kit+, or Lin− cells. 
     
     
         13 . The method of  claim 8 , wherein the conditions comprise culturing the cells in the presence of erythropoietin, Stem Cell Factor (SCF), Insulin-like Growth Factor 1 (IGF1) and a glucocorticoid. 
     
     
         14 . The method of  claim 13 , wherein the glucocorticoid is hydrocortisone or dexamethasone. 
     
     
         15 . The method of  claim 8 , wherein the starting population of cells is obtained from the subject. 
     
     
         16 . The method of  claim 8 , wherein the CDKi is inhibitor is roscovitine or SC-221409. 
     
     
         17 . A method of treating a subject who has a bone marrow failure syndrome (BMFS) or anemia, the method comprising administering to the subject a therapeutically effective amount of hematopoietic stem cells (HSCs) produced by:
 i) providing a starting population comprising bone marrow, mobilized peripheral blood, or umbilical cord blood, and   ii) maintaining the starting population in the presence of a sufficient amount of a Cyclin-Dependent Kinase inhibitor (CDKi) under conditions sufficient for generation and expansion of a desired number of HSCs.   
     
     
         18 . The method of  claim 17 , wherein the CDKi inhibits CDK2. 
     
     
         19 . The method of  claim 17 , wherein the conditions sufficient for generation and expansion of a desired number of HSCs comprise culture in the presence of one or more of five growth factors: SCF, IL-3, IL-6, G-CSF, and Flt3L. 
     
     
         20 . The method of  claim 17 , wherein the starting population of cells is obtained from the subject. 
     
     
         21 . The method of  claim 17 , wherein the CDKi is inhibitor is roscovitine or SC-221409.