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MicroRNA networks in FLT3-ITD acute myeloid leukemia
MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169767/ https://www.ncbi.nlm.nih.gov/pubmed/35412895 http://dx.doi.org/10.1073/pnas.2112482119 |
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author | Hoang, Dinh Hoa Zhao, Dandan Branciamore, Sergio Maestrini, Davide Rodriguez, Ivan R. Kuo, Ya-Huei Rockne, Russell Khaled, Samer K. Zhang, Bin Nguyen, Le Xuan Truong Marcucci, Guido |
author_facet | Hoang, Dinh Hoa Zhao, Dandan Branciamore, Sergio Maestrini, Davide Rodriguez, Ivan R. Kuo, Ya-Huei Rockne, Russell Khaled, Samer K. Zhang, Bin Nguyen, Le Xuan Truong Marcucci, Guido |
author_sort | Hoang, Dinh Hoa |
collection | PubMed |
description | MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). In fact, FLT3-ITD induces the expression of miR-155 through a noncanonical mechanism of miRNA biogenesis that implicates cytoplasmic Drosha ribonuclease III (DROSHA). In turn, miR-155 down-regulates SH2-containing inositol phosphatase 1 (SHIP1), thereby increasing phosphor-protein kinase B (AKT) that in turn serine-phosphorylates, stabilizes, and activates Sprouty related EVH1 domain containing 1 (SPRED1). Activated SPRED1 inhibits the RAN/XPO5 complex and blocks the nucleus-to-cytoplasm transport of pre-miR-126, which cannot then complete the last steps of biogenesis. The net result is aberrantly low levels of mature miR-126 that allow quiescent leukemia blasts to be recruited into the cell cycle and proliferate. Thus, miR-126 down-regulation in proliferating AML blasts is downstream of FLT3-ITD–dependent miR-155 expression that initiates a complex circuit of concatenated regulatory feedback (i.e., miR-126/SPRED1, miR-155/human dead-box protein 3 [DDX3X]) and feed-forward (i.e., miR-155/SHIP1/AKT/miR-126) regulatory loops that eventually converge into an output signal for leukemic growth. |
format | Online Article Text |
id | pubmed-9169767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-91697672022-10-11 MicroRNA networks in FLT3-ITD acute myeloid leukemia Hoang, Dinh Hoa Zhao, Dandan Branciamore, Sergio Maestrini, Davide Rodriguez, Ivan R. Kuo, Ya-Huei Rockne, Russell Khaled, Samer K. Zhang, Bin Nguyen, Le Xuan Truong Marcucci, Guido Proc Natl Acad Sci U S A Biological Sciences MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). In fact, FLT3-ITD induces the expression of miR-155 through a noncanonical mechanism of miRNA biogenesis that implicates cytoplasmic Drosha ribonuclease III (DROSHA). In turn, miR-155 down-regulates SH2-containing inositol phosphatase 1 (SHIP1), thereby increasing phosphor-protein kinase B (AKT) that in turn serine-phosphorylates, stabilizes, and activates Sprouty related EVH1 domain containing 1 (SPRED1). Activated SPRED1 inhibits the RAN/XPO5 complex and blocks the nucleus-to-cytoplasm transport of pre-miR-126, which cannot then complete the last steps of biogenesis. The net result is aberrantly low levels of mature miR-126 that allow quiescent leukemia blasts to be recruited into the cell cycle and proliferate. Thus, miR-126 down-regulation in proliferating AML blasts is downstream of FLT3-ITD–dependent miR-155 expression that initiates a complex circuit of concatenated regulatory feedback (i.e., miR-126/SPRED1, miR-155/human dead-box protein 3 [DDX3X]) and feed-forward (i.e., miR-155/SHIP1/AKT/miR-126) regulatory loops that eventually converge into an output signal for leukemic growth. National Academy of Sciences 2022-04-11 2022-04-19 /pmc/articles/PMC9169767/ /pubmed/35412895 http://dx.doi.org/10.1073/pnas.2112482119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Hoang, Dinh Hoa Zhao, Dandan Branciamore, Sergio Maestrini, Davide Rodriguez, Ivan R. Kuo, Ya-Huei Rockne, Russell Khaled, Samer K. Zhang, Bin Nguyen, Le Xuan Truong Marcucci, Guido MicroRNA networks in FLT3-ITD acute myeloid leukemia |
title | MicroRNA networks in FLT3-ITD acute myeloid leukemia |
title_full | MicroRNA networks in FLT3-ITD acute myeloid leukemia |
title_fullStr | MicroRNA networks in FLT3-ITD acute myeloid leukemia |
title_full_unstemmed | MicroRNA networks in FLT3-ITD acute myeloid leukemia |
title_short | MicroRNA networks in FLT3-ITD acute myeloid leukemia |
title_sort | microrna networks in flt3-itd acute myeloid leukemia |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169767/ https://www.ncbi.nlm.nih.gov/pubmed/35412895 http://dx.doi.org/10.1073/pnas.2112482119 |
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