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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy
Regardless of the fraction of acute lymphoblastic leukemia (ALL) cells evaluated, decreased BCL6 protein abundance was observed in ALL cells co-cultured with bone marrow stromal cells (BMSC) or Human osteoblasts (HOB), with the most pronounced reduction consistently observed in the phase dim (PD) population (Figure 1A-1B)
Consistent with western blot observations, flow cytometry and confocal microscopy analysis of REH and Nalm-27 cell lines showed that leukemic cells recovered from the PD population of BMSC or HOB co-culture had reduced BCL6 protein abundance compared to tumor cells cultured in media alone (Figure 1B and 1D)
Summary
While two-thirds of cases present in children, the risk of ALL increases with age in the adult population [1]. In both populations, relapse of disease is associated with poor prognosis, with relapsed disease often being more aggressive and refractory to treatment [2, 3]. Consistent with relapse in the bone marrow microenvironment (BMM), we and others have shown that bone marrow stromal cells (BMSC) and osteoblasts (HOB) provide protection to leukemic cells during chemotherapy treatment [8,9,10,11,12,13,14,15,16]. The cell signaling pathways by which the BMM influences tumor cells to provide this protection remains incompletely understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
