The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency induces Pelger-Huët anomaly and promotes sAML

• 成果类型: Article
• 署名作者: Xu, Song'en; Hong, Jiaxin; Dongye, Meimei; Lin, Jiehao; Xue, Rongtao; Huang, Zhibin; Xu, Jin; Zhang, Yiyue; Leung, Anskar Yu- Hung; Shen, Juan; Zhang, Wenqing; Liu, Wei
• 署名单位: South China University of Technology; Sun Yat Sen University; Southern Medical University - China; University of Hong Kong; Guangdong Pharmaceutical University; Guangdong Pharmaceutical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13161
• DOI: 10.1073/pnas.2416121122
• 发表日期: 2025-03-04
• 关键词: acute myeloid-leukemia; pseudo-pelger-huet; differentiation; chemotherapy; expression; mutations; induction; secondary; oncogene; roles

摘要

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-Hu & euml;t 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.