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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1926-1938
Number of pages13
JournalOncogene
Volume37
Issue number14
DOIs
StatePublished - Apr 1 2018

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MicroRNAs
Phosphotransferases
Cell Proliferation
B-Cell Leukemia
Porifera
B-Cell Lymphoma
Tumor Cell Line
Luciferases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma
Cell Survival
Leukemia
Down-Regulation
Apoptosis
Cell Line
Polymerase Chain Reaction
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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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. / Hu, Tianxiang; Chong, Yating; Qin, Haiyan; Kitamura, Eiko; Chang, Chang Sheng; Silva, Jeane; Ren, Mingqiang; Cowell, John K.

In: Oncogene, Vol. 37, No. 14, 01.04.2018, p. 1926-1938.

Research output: Contribution to journalArticle

Hu, Tianxiang ; Chong, Yating ; Qin, Haiyan ; Kitamura, Eiko ; Chang, Chang Sheng ; Silva, Jeane ; Ren, Mingqiang ; Cowell, John K. / The MIR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase. In: Oncogene. 2018 ; Vol. 37, No. 14. pp. 1926-1938.
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