1] Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China [2].
Cell Death Differ. 2014 Jan;21(1):100-12. doi: 10.1038/cdd.2013.133. Epub 2013 Sep 27.
Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia (AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34+ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy.
造血干/祖细胞的异常增殖、凋亡抑制和分化阻滞已被证实是导致急性髓系白血病（AML）的主要原因。先前的研究表明，miR-29a 和 miR-29b 可作为白血病发生过程中的肿瘤抑制因子。然而，miR-29 家族在 AML 发展中的功能和机制及其在 AML 治疗中的潜力仍需进一步研究。本研究报道，miR-29a、-29b 和 -29c 家族成员在 AML 患者外周血单个核细胞和骨髓（BM）CD34+细胞中的表达普遍下调，与健康供者相比。在 THP1 和 NB4 细胞中过表达每个 miR-29 成员均显著抑制细胞增殖并促进细胞凋亡。AKT2 和 CCND2 mRNAs 被证实是 miR-29 成员的靶标，miR-29 家族的作用归因于 Akt2 和 CCND2 这两个关键信号分子的减少。在 AML 病例中检测到显著增加的 Akt2、CCND2 和 c-Myc 水平，与 AML 原始细胞中 miR-29 表达的降低相关。此外，在髓系白血病发生中发现了包含 c-Myc、miR-29 家族和 Akt2 的反馈环。在 AML BM 原始细胞中重新引入每个 miR-29 成员部分纠正了异常细胞增殖、凋亡抑制和髓系分化阻滞。miR-29a、-29b 和 -29c 在 AML 模型小鼠中的静脉注射显著缓解了白血病症状。总之，我们的研究结果揭示了 miR-29 家族在 AML 发展中的关键作用，恢复 AML 患者中 miR-29 家族的表达可能为 AML 提供新的治疗策略。
