Sun et al. 2019 (PRJNA553142)

General Details

Title CircMYBL2 Regulates FLT3-ITD FLT3AML Translation in AML
Organism
Number of Samples 4
Release Date 2019/07/08 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP213599
ENA SRP213599
GEO GSE133925
BioProject PRJNA553142

Publication

Title
Authors Sun YM, Wang WT, Zeng ZC, Chen TQ, Han C, Pan Q, Huang W, Fang K, Sun LY, Zhou YF, Luo XQ, Luo C, Du X, Chen YQ
Journal Blood
Publication Date 2019 Oct 31
Abstract Internal tandem duplication (ITD) mutations within FMS-like tyrosine kinase-3 (FLT3) occur in up to 30% of acute myeloid leukemia (AML) patients and confer a very poor prognosis. The oncogenic form of FLT3 is an important therapeutic target, and inhibitors specifically targeting FLT3 kinase can induce complete remission; however, relapse after remission has been observed due to acquired resistance with secondary mutations in FLT3, highlighting the need for new strategies to target FLT3-ITD mutations. Recent studies have reported that the aberrant formations of circular RNAs (circRNAs) are biological tumorigenesis-relevant mechanisms and potential therapeutic targets. Herein, we discovered a circRNA, circMYBL2, derived from the cell-cycle checkpoint gene MYBL2. circMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo. Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of polypyrimidine tract-binding protein 1 (PTBP1) to FLT3 messenger RNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD+ cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for FLT3-ITD AML. © 2019 by The American Society of Hematology.
PMC PMC6839953
PMID 31387917
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR9651589 PRJNA553142 Homo sapiens MOLM13 0.0 Cycloheximide
SRR9651590 PRJNA553142 Homo sapiens MOLM13 0.0 Cycloheximide
SRR9651591 PRJNA553142 Homo sapiens MOLM13 0.0 Cycloheximide
SRR9651592 PRJNA553142 Homo sapiens MOLM13 0.0 Cycloheximide
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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