title: BCL6 modulation of acute lymphoblastic leukemia response to chemotherapy.
abstract: The bone marrow niche has a significant impact on acute lymphoblastic leukemia (ALL) cell phenotype. Of clinical relevance is the frequency with which quiescent leukemic cells, in this niche, survive treatment and contribute to relapse. This study suggests that marrow microenvironment regulation of BCL6 in ALL is one factor that may be involved in the transition between proliferative and quiescent states of ALL cells. Utilizing ALL cell lines, and primary patient tumor cells we observed that tumor cell BCL6 protein abundance is decreased in the presence of primary human bone marrow stromal cells (BMSC) and osteoblasts (HOB). Chemical inhibition, or shRNA knockdown, of BCL6 in ALL cells resulted in diminished ALL proliferation. As many chemotherapy regimens require tumor cell proliferation for optimal efficacy, we investigated the consequences of constitutive BCL6 expression in leukemic cells during co-culture with BMSC or HOB. Forced chronic expression of BCL6 during co-culture with BMSC or HOB sensitized the tumor to chemotherapy induced cell death. Combination treatment of caffeine, which increases BCL6 expression in ALL cells, with chemotherapy extended the event free survival of mice. These data suggest that BCL6 is one factor, modulated by microenvironment derived cues that may contribute to regulation of ALL therapeutic response.
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of The WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Slone
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of The WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Blake S
authors.initials: BS
authors.lastname: Moses
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of The WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.|Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Hare
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of The WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Evans
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of The WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Debbie
authors.initials: D
authors.lastname: Piktel
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of The WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.|Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051560:Proto-Oncogene Proteins c-bcl-6
keywords: BCL6; acute lymphoblastic leukemia; bone marrow microenvironment; chemotherapy resistance