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The miR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase

Oncogene volume 37, pages 1926–1938 (2018)Cite this article

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Abstract

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.

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Fig. 1: Identification of miRNAs regulated by chimeric FGFR1 kinase.
Fig. 2: Forced expression of miRNA-17/92 promotes growth in BCR-FGFR1-expressing B-lymphoma cells.
Fig. 3: Inhibition of the miR-17/92 family members leads to suppression of cell growth and increases apoptosis.
Fig. 4: Forced expression of members of the miR-17/92 cluster can ameliorate BGJ398 suppression of FGFR1 activation.
Fig. 5: Regulation of miR-17/92 expression by FGFR1.
Fig. 6: miR-17/92 targets CDKN1A and PTEN in FGFR1-driven leukemogenesis
Fig. 7: Manipulation of miR-17/92 affects FGFR1-driven leukemogenesis in vivo.

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Acknowledgements

This work was supported by grant CA076167 from the National Institutes of Health.

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  1. John K Cowell

    Present address: Consortium for Health and Military Performance, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

Authors and Affiliations

  1. Georgia Cancer Center, Augusta University, Augusta, GA, USA

    Tianxiang Hu, Yating Chong, Haiyan Qin, Eiko Kitamura, Chang-Sheng Chang, Jeane Silva, Mingqiang Ren & John K Cowell

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Hu, T., Chong, Y., Qin, H. et al. The miR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase. Oncogene 37, 1926–1938 (2018). https://doi.org/10.1038/s41388-017-0091-1

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