PUBLICATION
The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency induces Pelger-Huët anomaly and promotes sAML
- Authors
- Xu, S., Hong, J., Dongye, M., Lin, J., Xue, R., Huang, Z., Xu, J., Zhang, Y., Leung, A.Y., Shen, J., Zhang, W., Liu, W.
- ID
- ZDB-PUB-250303-2
- Date
- 2025
- Source
- Proceedings of the National Academy of Sciences of the United States of America 122: e2416121122e2416121122 (Journal)
- Registered Authors
- Huang, Zhibin, Leung, Anskar, Xue, Rongtao, Xu, Jin, Zhang, Wenqing, Zhang, Yiyue
- Keywords
- Pelger?Huët anomaly cells, Pu.1, c-Myb, sAML, zebrafish
- Datasets
- GEO:GSE206979
- MeSH Terms
-
- Humans
- Mutation
- Leukemia, Myeloid, Acute*/genetics
- Leukemia, Myeloid, Acute*/metabolism
- Leukemia, Myeloid, Acute*/pathology
- Trans-Activators*/genetics
- Trans-Activators*/metabolism
- Male
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/metabolism
- Myelodysplastic Syndromes/pathology
- Neutrophils/metabolism
- Pelger-Huet Anomaly*/genetics
- Pelger-Huet Anomaly*/metabolism
- Animals
- Proto-Oncogene Proteins*/genetics
- Proto-Oncogene Proteins*/metabolism
- Zebrafish*
- Proto-Oncogene Proteins c-myb*/genetics
- Proto-Oncogene Proteins c-myb*/metabolism
- PubMed
- 40020188 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Xu, S., Hong, J., Dongye, M., Lin, J., Xue, R., Huang, Z., Xu, J., Zhang, Y., Leung, A.Y., Shen, J., Zhang, W., Liu, W. (2025) The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency induces Pelger-Huët anomaly and promotes sAML. Proceedings of the National Academy of Sciences of the United States of America. 122:e2416121122e2416121122.
Abstract
Approximately 30% of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML) via accumulating gene mutations. Genomic analyses reveal a complex interplay among mutant genes, with co-occurring and mutually exclusive patterns. Hyperactivation of c-MYB and deficiency of PU.1 have been linked to myeloid disorders. We report a case of AML with concurrent PU.1 and c-MYB mutations, exhibiting early onset, high blast count, chemo-resistance, indicating high-risk features, along with elevated Pelger-Huët anomaly (PHA). However, the synergistic mechanism of c-MYB and PU.1 in sAML remains unclear. Using c-Myb-hyperactivation and Pu.1-deficient double-strain (c-mybhyper;pu.1G242D/G242D) zebrafish, we investigated MDS/sAML progression. Surprisingly, the double mutant exhibited a distinct type of neutrophil resembling clinical PHA cells and demonstrated a higher rate of MDS/sAML transformation. Further expression analysis revealed reduced lmnb1 expression in double-mutant zebrafish. Knockdown of lmnb1 resulted in PHA and increased blast cells, while overexpression of lmnb1 in c-mybhyper;pu.1G242D/G242D reduced PHA cell level. This suggests that c-Myb hyperactivation and Pu.1 deficiency synergistically reduce lmnb1 expression, inducing the development of PHA-like neutrophils and promoting MDS/sAML progression in zebrafish. Moreover, coadministration of cell cycle inhibitor cytarabine (Ara-C) and the differential inducer all-trans retinoic acid (ATRA) could effectively relieve the neutrophil expansion and PHA symptoms in c-mybhyper;pu.1G242D/G242D zebrafish. Our findings revealed that c-Myb hyperactivation and Pu.1 deficiency played a synergistic role in sAML development and suggests a phenotypic association between the emergence of PH-like cells and the transformation to sAML. Furthermore, c-mybhyper;pu.1G242D/G242D zebrafish might serve as a suitable sAML model for drug screening.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping