title: Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia.
abstract: Acute lymphoblastic leukemia (ALL) has many features in common with normal B-cell progenitors, including their ability to respond to diverse signals from the bone marrow microenvironment (BMM) resulting in regulation of cell-cycle progression and survival. Bone marrow-derived cues influence many elements of both steady state hematopoiesis and hematopoietic tumor cell phenotypes through modulation of gene expression. miRNAs are one regulatory class of small noncoding RNAs that have been shown to be increasingly important in diverse settings of malignancy. In the current study, miRNA profiles were globally altered in ALL cells following exposure to primary human bone marrow niche cells, including bone marrow stromal cells (BMSC) and primary human osteoblasts (HOB). Specifically, mature miR-221 and miR-222 transcripts were decreased in ALL cells cocultured with BMSC or HOB, coincident with increased p27 (CDKN1B), a previously validated target. Increased p27 protein in ALL cells exposed to BMSC or HOB is consistent with accumulation of tumor cells in the G0phase of the cell cycle and resistance to chemotherapy-induced death. Overexpression of miR-221 in ALL cells during BMSC or HOB coculture prompted cell-cycle progression and sensitization of ALL cells to cytotoxic agents, blunting the protective influence of the BMM. These novel observations indicate that BMM regulation of miR-221/222 contributes to marrow niche-supported tumor cell quiescence and survival of residual cells.
  
  
  
  Niche-influenced miR-221/222 may define a novel therapeutic target in ALL to be combined with existing cytotoxic agents to more effectively eradicate refractory disease that contributes to relapse. Mol Cancer Res; 14(10); 909-19. ©2016 AACR.
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Blake S
authors.initials: BS
authors.lastname: Moses
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Evans
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: William L
authors.initials: WL
authors.lastname: Slone
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Debbie
authors.initials: D
authors.lastname: Piktel
authors.affiliation: Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Martinez
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Craig
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia. lgibson@hsc.wvu.edu.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D049109:Cell Proliferation; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D055153:Stem Cell Niche
chemical_list: D035683:MicroRNAs; C525709:MIR221, human; C525710:MIR222, human