Open AccessCytoplasmic DROSHA and non-canonical mechanisms of MiR-155 biogenesis in FLT3-ITD acute myeloid leukemia
Author(s) -
Le Xuan Truong Nguyen,
Bin Zhang,
Dinh Hoa Hoang,
Dandan Zhao,
Huafeng Wang,
Herman Wu,
YuLin Su,
Haojie Dong,
Sonia Rodriguez-Rodriguez,
Brian Armstrong,
Lucy Ghoda,
Danilo Perrotti,
Flavia Pichiorri,
Jianjun Chen,
Ling Li,
Marcin Kortylewski,
Russell C. Rockne,
YaHuei Kuo,
Samer K. Khaled,
Nadia Carlesso,
Guido Marcucci
Publication year - 2021
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-021-01166-9
Subject(s) - drosha , myeloid leukemia , non canonical , biogenesis , leukemia , myeloid , cancer research , biology , medicine , genetics , microbiology and biotechnology , gene , rna , rna interference
We report here on a novel pro-leukemogenic role of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) that interferes with microRNAs (miRNAs) biogenesis in acute myeloid leukemia (AML) blasts. We showed that FLT3-ITD interferes with the canonical biogenesis of intron-hosted miRNAs such as miR-126, by phosphorylating SPRED1 protein and inhibiting the "gatekeeper" Exportin 5 (XPO5)/RAN-GTP complex that regulates the nucleus-to-cytoplasm transport of pre-miRNAs for completion of maturation into mature miRNAs. Of note, despite the blockage of "canonical" miRNA biogenesis, miR-155 remains upregulated in FLT3-ITD+ AML blasts, suggesting activation of alternative mechanisms of miRNA biogenesis that circumvent the XPO5/RAN-GTP blockage. MiR-155, a BIC-155 long noncoding (lnc) RNA-hosted oncogenic miRNA, has previously been implicated in FLT3-ITD+ AML blast hyperproliferation. We showed that FLT3-ITD upregulates miR-155 by inhibiting DDX3X, a protein implicated in the splicing of lncRNAs, via p-AKT. Inhibition of DDX3X increases unspliced BIC-155 that is then shuttled by NXF1 from the nucleus to the cytoplasm, where it is processed into mature miR-155 by cytoplasmic DROSHA, thereby bypassing the XPO5/RAN-GTP blockage via "non-canonical" mechanisms of miRNA biogenesis.