Department of Hematology, Chinese PLA General Hospital, Beijing, China.
Oncogene. 2012 Jan 26;31(4):507-17. doi: 10.1038/onc.2011.248. Epub 2011 Jun 27.
Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL-AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL-AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3' untranslated regions may modulate MLL-AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL-AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL-AF4 expression in MLL-AF4 ALL samples. Restoration of miR-143 in MLL-AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL-AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL-AF4-negative primary blasts, which was directly associated with expression of the MLL-AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL-AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL-AF4 B-cell ALL.
融合蛋白含有混合谱系白血病（MLL）的氨基末端是常见的急性淋巴细胞白血病（ALL）由于易位。MLL-AF4 融合蛋白是由易位 t（4;11）（q21;q23）产生的，并且 t（4;11）阳性 ALL 患者（MLL-AF4 ALL）与具有其他 MLL 相关白血病的患者相比，预后明显较差。这种融合蛋白在白血病发生中的详细作用尚不清楚。针对 AF4 3'非翻译区的 microRNAs（miRNAs）可能调节 MLL-AF4 融合蛋白水平，这就提出了一个问题，即这些 miRNAs 的调节是否参与了 MLL-AF4 ALL 的进展。在这项研究中，我们表明 miR-143 被鉴定为 MLL-AF4 ALL 样本中 MLL-AF4 表达的调节剂。在 MLL-AF4 阳性 RS4;11 和 MV4-11 细胞中恢复 miR-143 诱导细胞凋亡，通过降低 MLL-AF4 融合蛋白水平对白血病细胞生长产生负面影响。此外，miR-143 在 MLL-AF4 阳性原代细胞和细胞系中由于启动子超甲基化而被表观遗传抑制，但在正常骨髓细胞和 MLL-AF4 阴性原代细胞中没有，这与 MLL-AF4 癌基因的表达直接相关。这是第一项表明 miR-143 在 MLL-AF4 B 细胞 ALL 中作为肿瘤抑制因子发挥作用的研究。这些数据揭示了上调 miR-143 表达对 MLL-AF4 B 细胞 ALL 的治疗潜力。
