Primary human AML cells with higher levels of BCL6 expression displayed sensitivity when exposed to BCL6 inhibitors.
BCL6 induction contributed to cytarabine resistance, and inhibition of BCL6 in AML cells decreased LSC activity
BCL6 is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed induction of BCL6 repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitor induced apoptosis and decreased colony forming capacity which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in significant reduction of leukemia initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal HSCs. Treatment with cytarabine (AraC) further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML patient derived xenografts (PDX) with BCL6 inhibitor plus Ara-C suggested enhanced anti-leukemia activity by this combination. Hence pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.