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.

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia

“…Coculture Study. Coculture conditions have been previously described (Slone et al, 2016b). Briefly, 1 Â 10 6 REH or REH/Ara-C cells were seeded on either BMSC or HOB adherent layers and Fig.…”

“…To study drug resistance in leukemic cells, we previously developed an in vitro coculture model consisting of humanderived ALL cells cultured in the presence of either primary human bone marrow stromal cells (BMSCs) or primary human osteoblasts (HOBs) (Moses et al, 2016b). Using this model, we developed a protocol to isolate and characterize a subset of phase dim (PD) leukemic cells buried under the BM-derived adherent layer (Slone et al, 2016b). PD cells share the characteristics typical of relapsed/refractory leukemic cells, in that they are quiescent and resistant to chemotherapy, have impaired microRNA biogenesis, and are relevant to the current study on manifested altered mitochondrial metabolism (Moses et al, 2016a,b;Slone et al, 2016a).…”

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

“…The leukemic cells which were buried under the BMSC were separated by size exclusion with G10 sephadex after vigorous washing to remove all leukemic cells adhered to the top of the BMSC [9]. Buried leukemic cells were designated phase dim cells (PD) and have been previously described to be the most chemotherapy-resistant population [11, 12]. As such, they are not assumed to be identical, but rather are used as a model, for refractory tumor cells that are known to be clinically problematic in the treatment of ALL.…”

Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia

“…The PD tumor cells are used to model cells that contribute to MRD in vivo based on phenotypic similarities [9]. Using this niche-based co-culture model, we have reported that primary ALL samples, or ALL cells in co-culture with the BM cellular components, have reduced BCL6 expression in the PD cell population [10]. Furthermore, reduction in BCL6 resulted in disruption of cell cycle progression, with cyclin D3-dependent accumulation of cells in the G0/G1 phase.…”

“…Furthermore, reduction in BCL6 resulted in disruption of cell cycle progression, with cyclin D3-dependent accumulation of cells in the G0/G1 phase. The importance of BCL6 in maintaining cell quiescence, drug resistance and the resulting MDR phenotype was further validated in vivo by demonstrating significant event free survival in mice treated with a combination of caffeine (stabilizer of BCL6) and cyatarabine (Ara-C) when compared to mice treated with Ara-C alone [10]. BCL6 has also been shown to be a master regulator of glycolysis by directly repressing the overall gene program of the glycolytic pathway [11].…”