MicroRNAs (miRNAs) have pathogenic roles in the development of a variety of leukemias. Here we identify miRNAs that have important roles in the development of B lymphomas resulting from the expression of the chimeric BCR-FGFR1 kinase. The miR-17/92 cluster was particularly implicated and forced expression resulted in increased cell proliferation, while inhibiting its function using miRNA sponges reduced cell growth and induced apoptosis. Cells treated with the potent BGJ389 FGFR1 inhibitor led to miR-17/92 downregulation, suggesting regulation by FGFR1. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-17/92 expression in stable transduced cell lines demonstrated that BCR-FGFR1 can regulate miR-17/92 expression. This positive association of miR-17/92 with BCR-FGFR1 was also confirmed in primary mouse SCLL tissues and primary human CLL samples. miR-17/92 promotes cell proliferation and survival by targeting CDKN1A and PTEN in B-lymphoma cell lines and primary tumors. An inverse correlation in expression levels was seen between miR-17/92 and both CDKN1A and PTEN in two cohorts of CLL patients. Finally, in vivo engraftment studies demonstrated that manipulation of miR-17/92 was sufficient to affect BCR-FGFR1-driven leukemogenesis. Overall, our results define miR-17/92 as a downstream effector of FGFR1 in BCR-FGFR1-driven B-cell lymphoblastic leukemia.

中文翻译：

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miR-17 / 92簇涉及由BCR-FGFR1嵌合激酶驱动的SCLL综合征的分子病因。

MicroRNA（miRNA）在多种白血病的发生中具有致病作用。在这里，我们确定了在嵌合BCR-FGFR1激酶的表达导致的B淋巴瘤的发展中具有重要作用的miRNA。尤其牵涉到miR-17 / 92簇，强迫表达导致细胞增殖增加，而使用miRNA海绵抑制其功能则降低了细胞生长并诱导了细胞凋亡。用有效的BGJ389 FGFR1抑制剂处理的细胞导致miR-17 / 92下调，提示受FGFR1调节。稳定转导的细胞系中内源性miR-17 / 92表达的瞬时荧光素酶报告基因分析和qRT-PCR检测证明BCR-FGFR1可以调节miR-17 / 92的表达。miR-17 / 92与BCR-FGFR1的这种正相关性在原代小鼠SCLL组织和原代人CLL样品中也得到了证实。miR-17 / 92通过靶向B淋巴瘤细胞系和原发性肿瘤中的CDKN1A和PTEN来促进细胞增殖和存活。在两个CLL患者队列中，miR-17 / 92与CDKN1A和PTEN两者之间的表达水平呈负相关。最后，体内植入研究表明，miR-17 / 92的操纵足以影响BCR-FGFR1驱动的白血病发生。总体而言，我们的结果将miR-17 / 92定义为BCR-FGFR1驱动的B细胞淋巴细胞白血病中FGFR1的下游效应子。在两个CLL患者队列中，miR-17 / 92与CDKN1A和PTEN两者之间的表达水平呈负相关。最后，体内植入研究表明，miR-17 / 92的操纵足以影响BCR-FGFR1驱动的白血病发生。总体而言，我们的结果将miR-17 / 92定义为BCR-FGFR1驱动的B细胞淋巴细胞白血病中FGFR1的下游效应子。在两个CLL患者队列中，miR-17 / 92与CDKN1A和PTEN两者之间的表达水平呈负相关。最后，体内植入研究表明，miR-17 / 92的操纵足以影响BCR-FGFR1驱动的白血病发生。总体而言，我们的结果将miR-17 / 92定义为BCR-FGFR1驱动的B细胞淋巴细胞白血病中FGFR1的下游效应子。