Merkel Olaf, Hamacher Frank, Griessl Robert, Grabner Lisa, Schiefer Ana-Iris, Prutsch Nicole, Baer Constance, Egger Gerda, Schlederer Michaela, Krenn Peter William, Hartmann Tanja Nicole, Simonitsch-Klupp Ingrid, Plass Christoph, Staber Philipp Bernhard, Moriggl Richard, Turner Suzanne D, Greil Richard, Kenner Lukas
Department of Translational Oncology, National Centre for Tumour Diseases (NCT), German Cancer Research Centre (DKFZ), Heidelberg, Germany.
Department of Clinical Pathology, Medical University Vienna, Austria.
J Pathol. 2015 Aug;236(4):445-56. doi: 10.1002/path.4539. Epub 2015 Apr 27.
Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).
间变性大细胞淋巴瘤（ALCL）是一种罕见的侵袭性非霍奇金淋巴瘤，其特征为CD30表达以及在年轻患者中发病。约一半的ALCL患者存在t(2;5)(p23;q35)易位，这导致核磷蛋白-间变性淋巴瘤酪氨酸激酶（NPM-ALK）融合蛋白的形成（ALK阳性ALCL）。然而，对于预后较差的ALK阴性ALCL（ALK阴性ALCL）的分子特征和肿瘤驱动因素知之甚少。我们发现，与ALK阳性ALCL相反，ALK阴性ALCL淋巴瘤显示出高miR-155表达。与此一致，我们观察到ALCL中miR-155启动子甲基化与miR-155表达呈负相关。然而，未观察到ALK激酶对miR-155水平有直接影响。AGO2免疫沉淀显示miR-155是最丰富的miRNA，并富集了靶mRNA C/EBPβ和SOCS1。为了研究其功能，我们在ALK阳性ALCL细胞系中过表达miR-155，并证明C/EBPβ和SOCS1水平降低。在ALK阴性ALCL的小鼠移植模型中，我们表明抗miR-155模拟物能够减少肿瘤生长。这与这些肿瘤中裂解的半胱天冬酶-3水平升高和SOCS1水平升高相伴，从而导致STAT3信号传导受到抑制。此外，miR-155诱导IL-22表达并抑制C/EBPβ靶标IL-8。这些数据表明，miR-155可作为ALK阴性ALCL中的肿瘤驱动因素，阻断miR-155可能具有治疗意义。原始miRNA阵列数据见补充材料（表S1）。
