BCL6 modulation of acute lymphoblastic leukemia response to chemotherapy
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William L. Slone1, Blake S. Moses1, Ian Hare1,2, Rebecca Evans1, Debbie Piktel1 and Laura F. Gibson1,2
1 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
2 Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA
Laura F. Gibson, email:
Keywords: bone marrow microenvironment, acute lymphoblastic leukemia, BCL6, chemotherapy resistance
Received: February 25, 2016 Accepted: February 28, 2016 Published: March 22, 2016
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.
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