MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression
MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression
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DOI：
10.1182/blood-2010-09-301994
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发表时间：
2011-06-16
期刊：
影响因子：
20.3
通讯作者：
Lamant, Laurence
中科院分区：
文献类型：
--
作者：
Desjobert, Cecile;Renalier, Marie-Helene;Lamant, Laurence
尽管在实体癌和白血病中描述了特定microRNA（miRNA）的表达失调，但在ALK阳性（ALK（+））间变性大细胞淋巴瘤（ALCL）中几乎没有报道miRNA失调的证据。这些肿瘤过表达主要的抗凋亡蛋白髓细胞白血病1（MCL-1），这种情况可以弥补BCL-2的缺乏。我们报告ALK（+）ALCL细胞系和活检标本（n = 20）表达低水平的miR-29 a，这种下调需要活性NPM-ALK激酶。允许条件性NPM-ALK融合蛋白表达的小鼠模型（转基因小鼠和小鼠胚胎成纤维细胞[MEF]细胞）显示，在不存在NPM-ALK的情况下，miR-29 a表达增加。在NPM-ALK（+）ALCL细胞系中消除NPM-ALK激酶活性（siALK或PF-2341066）后，观察到一致的结果。此外，我们发现，miR-29 a的低表达，可能通过甲基化抑制，在MCL-1过表达中起着重要的调节作用，可以通过抑制凋亡促进肿瘤细胞的存活。在ALCL细胞系和异种移植模型中，发现增强的miR-29 a表达通过抑制MCL-1表达来调节细胞凋亡，伴随着肿瘤生长减少。因此，合成的miR-29 a代表了影响这些淋巴瘤中肿瘤发生的潜在新工具。（血。2011;117（24）：6627-6637）
Although deregulated expression of specific microRNAs (miRNAs) has been described in solid cancers and leukemias, little evidence of miRNA deregulation has been reported in ALK-positive (ALK(+)) anaplastic large cell lymphomas (ALCL). These tumors overexpress the major antiapoptotic protein myeloid cell leukemia 1 (MCL-1), a situation that could compensate for the lack of BCL-2. We report that ALK(+) ALCL cell lines and biopsy specimens (n = 20) express a low level of miR-29a and that this down-modulation requires an active NPM-ALK kinase. Murine models (transgenic mice and mouse embryonic fibroblast [MEF] cells), which allow conditional NPM-ALK fusion protein expression, showed an increase of miR-29a expression in the absence of NPM-ALK. Concordant results were observed after the abolition of NPM-ALK kinase activity (siALK or PF-2341066) in NPM-ALK(+) ALCL cell lines. In addition, we showed that low expression of miR-29a, probably through methylation repression, plays an important regulatory role in MCL-1 overexpression that could promote tumor cell survival by inhibiting apoptosis. Enforced miR-29a expression was found to modulate apoptosis through inhibition of MCL-1 expression in ALCL cell lines and in a xenografted model, with a concomitant tumor growth reduction. Thus, synthetic miR-29a represents a potential new tool to affect tumorigenesis in these lymphomas.(Blood. 2011;117(24):6627-6637)