MicroRNA 339 promotes development of Stem Cell Leukemia/Lymphoma syndrome via downregulation of the BCL2L11 and BAX pro-apoptotic genes

Development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of activated FGFR1 kinase on gene transcription, including dysregulation of microRNAs. In a screen for miRNAs that are directly regulated by FGFR1 and that stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhanced cell survival, wherease inhibition of its function reduced cell viability. miR-339-5p overexpression also protected cells from the effects of FGFR1 inactivation, promoting cell cycle progression and reducing apoptosis. BCR-FGFR1 fusion directly regulated miR-339-5p expression in cells lines; this correlation between miR-339-5p and FGFR1 expression was also observed in primary human B cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the pro-apoptotic genes BCL2L11 and BAX. In vivo, SCLL cells forced to overexpress miR-339-5p exhibited a more rapid onset of disease and poorer survival compared with cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL showed significantly higher expression of miR339-5p compared with two cohorts of CLL patient samples, suggesting direct roles for miR339-5p in disease progression and supporting the evidence generated in mouse models of SCLL.

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