Nature communications, 2021-10, Vol.12 (1), p.6154-6154, Article 6154
- Zhang, Lianjun
- Nguyen, Le Xuan Truong
- Chen, Ying-Chieh
- Wu, Dijiong
- Cook, Guerry J
- Hoang, Dinh Hoa
- Brewer, Casey J
- He, Xin
- Dong, Haojie
- Li, Shu
- Li, Man
- Zhao, Dandan
- Qi, Jing
- Hua, Wei-Kai
- Cai, Qi
- Carnahan, Emily
- Chen, Wei
- Wu, Xiwei
- Swiderski, Piotr
- Rockne, Russell C
- Kortylewski, Marcin
- Li, Ling
- Zhang, Bin
- Marcucci, Guido
- Kuo, Ya-Huei
2021
Details
- Autor(en) / Beteiligte
- Zhang, Lianjun
- Nguyen, Le Xuan Truong
- Chen, Ying-Chieh
- Wu, Dijiong
- Cook, Guerry J
- Hoang, Dinh Hoa
- Brewer, Casey J
- He, Xin
- Dong, Haojie
- Li, Shu
- Li, Man
- Zhao, Dandan
- Qi, Jing
- Hua, Wei-Kai
- Cai, Qi
- Carnahan, Emily
- Chen, Wei
- Wu, Xiwei
- Swiderski, Piotr
- Rockne, Russell C
- Kortylewski, Marcin
- Li, Ling
- Zhang, Bin
- Marcucci, Guido
- Kuo, Ya-Huei
- Titel
- Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance
- Ist Teil von
- Nature communications, 2021-10, Vol.12 (1), p.6154-6154, Article 6154
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-021-26420-7Titel-ID: cdi_doaj_primary_oai_doaj_org_article_ba8150db19cd424e95fcc1bef2ef61ff
- Format
- –
- Schlagworte
- Acute myeloid leukemia, Animal models, Animals, Antineoplastic Agents - pharmacology, Antineoplastic Agents - therapeutic use, Calcium-Binding Proteins - genetics, Cell Cycle Proteins - metabolism, Cell survival, Cell Survival - drug effects, Chemotherapy, Chromosome Inversion - genetics, Chromosomes, Human, Pair 16 - genetics, Depletion, EGF Family of Proteins - genetics, Fusion protein, GATA2 Transcription Factor - genetics, Gene expression, Guanine Nucleotide Exchange Factors - metabolism, Histone Deacetylases - metabolism, Humans, Karyopherins - metabolism, Leukemia, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - genetics, Leukemia, Myeloid, Acute - metabolism, Leukemia, Myeloid, Acute - pathology, Leukemogenesis, Maintenance, Mice, MicroRNAs - antagonists & inhibitors, MicroRNAs - genetics, MicroRNAs - metabolism, Molecular Targeted Therapy, Myc protein, Myeloid leukemia, Myeloid Progenitor Cells - drug effects, Myeloid Progenitor Cells - metabolism, Myeloid Progenitor Cells - pathology, Neoplastic Stem Cells - drug effects, Neoplastic Stem Cells - metabolism, Neoplastic Stem Cells - pathology, Nuclear Proteins - metabolism, Oncogene Proteins, Fusion - genetics, Oncogene Proteins, Fusion - metabolism, Progenitor cells, ran GTP-Binding Protein - metabolism, Repressor Proteins - metabolism, Stem cells, Survival, Therapeutic targets, Transcription, Xenograft Model Antitumor Assays, Xenografts, Xenotransplantation