BCL6 modulation in ALL

Bone Marrow Microenvironment influence over Leukemia Quiescence and Chemotherapy Resistance through Modulation of BCL6  

The bone marrow (BM) microenvironment is important in regulating ALL cell quiescence and proliferation. In order to design innovative therapies, a better understanding of the mechanisms by which this regulation occurs is needed. Of clinical relevance is the frequency with which quiescent leukemic cells survive treatment, initiate proliferation, and contribute to relapse of aggressive disease. Data from our laboratory suggest that the BM microenvironment’s regulation of BCL6 in leukemic cells is one factor involved in the transition between the proliferative and quiescent states of ALL. Observations suggests that ALL cell BCL6 protein expression is influenced due to primary human bone marrow stromal cell (BMSC) and osteoblast (HOB) derived signals. Leukemic cells with decreased BCL6 are characterized by diminished proliferation, G0 accumulation, and chemotherapy resistance. Conversely, removal of ALL cells from BM microenvironment stroma results in leukemic cells with increased BCL6 expression that are proliferative and sensitive to chemotherapy. Chemical inhibition or knock-down of BCL6 by shRNA in ALL cells results in diminished proliferation and chemotherapy resistance. As many chemotherapy regimens require tumor cell proliferation for optimal efficacy, we investigate the consequences of forced BCL6 expression in leukemic cells when in the protective BM microenvironment niche. Data suggests that forcing leukemic cells to express BCL6 when co-cultured with HOB or BMSC sensitizes the tumor to chemotherapy induced cell death. These data suggest that BCL6 is one factor, modulated by microenvironment derived cues that may contribute to regulation of ALL cell cycle progression and subsequently therapeutic response. We are hopeful that this mechanistic insight will contribute to design of novel treatment strategies that disrupt protective microenvironment signaling, with a goal of less intensive therapies for childhood ALL that reduce long-term effects and treatment induced secondary malignancies.