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Published on: February 21, 2018
The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency induces Pelger-Huët anomaly and promotes sAML
Song'en Xu1, Jiaxin Hong1, Meimei Dongye2
1Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou 510006, China.
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.
Insights
Concurrent mutations in PU.1 and c-MYB drive high-risk myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Zebrafish models reveal reduced Lmnb1 expression and Pelger-Huët anomaly (PHA) as key mechanisms, offering new therapeutic targets.
Area of Science:
- Hematology and Oncology
- Molecular Biology
- Zebrafish Genetics
Background:
- Myelodysplastic syndrome (MDS) frequently progresses to secondary acute myeloid leukemia (sAML) due to accumulating gene mutations.
- Concurrent mutations in c-MYB (hyperactivation) and PU.1 (deficiency) are implicated in myeloid disorders, but their synergistic role in sAML is unclear.
- A patient case presented with concurrent PU.1 and c-MYB mutations, high-risk AML features, and Pelger-Huët anomaly (PHA).
Purpose of the Study:
- To investigate the synergistic mechanism of c-MYB hyperactivation and PU.1 deficiency in MDS/sAML progression.
- To explore the role of Lmnb1 expression in this process.
- To evaluate potential therapeutic strategies using a zebrafish model.
Main Methods:
- Generation and analysis of a double-mutant zebrafish model with c-Myb hyperactivation and Pu.1 deficiency (c-myb).
- Phenotypic characterization of neutrophils and assessment of MDS/sAML transformation rates.
- Gene expression analysis (lmnb1), knockdown, and overexpression studies.
- Pharmacological intervention using cytarabine (Ara-C) and all-trans retinoic acid (ATRA).
Main Results:
- The c-myb zebrafish model exhibited unique neutrophils resembling PHA cells and a higher rate of MDS/sAML transformation.
- Reduced lmnb1 expression was observed in double-mutant zebrafish, and its manipulation recapitulated PHA and increased blast cells.
- Overexpression of lmnb1 ameliorated PHA in c-myb zebrafish, suggesting c-Myb/Pu.1 synergy reduces lmnb1.
- Combined Ara-C and ATRA treatment effectively reduced neutrophil expansion and PHA symptoms in c-myb zebrafish.
Conclusions:
- c-Myb hyperactivation and Pu.1 deficiency synergistically reduce lmnb1 expression, promoting PHA-like neutrophils and MDS/sAML progression.
- A phenotypic association exists between PHA-like cells and sAML transformation.
- The c-myb zebrafish model is a valuable tool for sAML research and drug screening.
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