The Synergistic Effect of C-Myb Hyperactivation and Pu.1 Deficiency Induces Pelger-Huët Anomaly and Promotes SAML

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2025 Feb 28

PMID 40020188

Authors

Songen Xu

Jiaxin Hong

Meimei Dongye

Jiehao Lin

Rongtao Xue

Zhibin Huang

Jin Xu

Yiyue Zhang

Anskar Yu-Hung Leung

Juan Shen

Wenqing Zhang

Wei Liu

Affiliations

Soon will be listed here.

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 and 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 and in sAML remains unclear. Using c-Myb-hyperactivation and Pu.1-deficient double-strain () 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 expression in double-mutant zebrafish. Knockdown of resulted in PHA and increased blast cells, while overexpression of in reduced PHA cell level. This suggests that c-Myb hyperactivation and Pu.1 deficiency synergistically reduce 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 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, zebrafish might serve as a suitable sAML model for drug screening.

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