BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.
BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.
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DOI：
10.1182/blood.2019001745
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发表时间：
2021-02-11
期刊：
影响因子：
20.3
通讯作者：
Guzman, Monica L
中科院分区：
文献类型：
--
作者：
Kawabata, Kimihito C;Zong, Hongliang;Guzman, Monica L
B细胞淋巴瘤6（BCL 6）是一种转录抑制因子和原癌基因，在先天性和适应性免疫系统和淋巴肿瘤中起着至关重要的作用。然而，其在骨髓恶性肿瘤中的作用仍不清楚。在这里，我们探讨了BCL 6在急性髓细胞白血病（AML）中的作用。BCL 6在AML细胞系和原发性AML样品中以可变且通常高水平表达。BCL 6水平较高的AML通常对BCL 6抑制剂治疗敏感，单核细胞分化的AML除外。用BCL 6抑制剂处理的AML细胞的基因表达谱显示了BCL 6抑制的靶基因的诱导和与DNA损伤检查点和干细胞基因下调相关的转录程序。用BCL 6抑制剂体外处理原代AML细胞可诱导细胞凋亡并降低集落形成能力，这与BCL 6表达水平相关。重要的是，原代AML细胞中BCL 6的抑制或敲低导致小鼠白血病引发能力的显著降低，表明白血病再增殖细胞功能的消除。相反，BCL 6敲除或抑制不会抑制正常造血干细胞的功能。阿糖胞苷治疗进一步诱导BCL 6表达，BCL 6诱导水平与阿糖胞苷耐药相关。用BCL 6抑制剂加阿糖胞苷治疗AML患者来源的异种移植物表明该组合具有增强的抗白血病活性。因此，BCL 6的药理学抑制可能提供一种新的治疗策略，用于消融白血病再增殖细胞和增加对化疗的反应性。
B-cell lymphoma 6 (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 a 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 inhibitors 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 a 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 hematopoietic stem cells. Treatment with cytarabine further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to cytarabine. Treatment of AML patient-derived xenografts with BCL6 inhibitor plus cytarabine suggested enhanced antileukemia activity with this combination. Hence, pharmacologic inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.