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The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency in inducing Pelger-Huët anomaly and promoting sAML transformation

ABSTRACT: Patients with acute myeloid leukemia developed from myelodysplastic syndrome (MDS/AML) have poor prognosis with more complex genetic mutations. Genomic analyses have shown complex association among mutant genes, including co-occurring and mutually exclusive. It has been reported that hyperactivation of MYB or deficiency of PU.1 could induce myeloid preleukemia. The simultaneous abnormal expression of these two proteins has been documented in some AML patients. However, the association of MYB and PU.1 in the pathogenesis of malignant hematopoiesis remains unclear. In this study, we used the c-Myb-hyperactivation and Pu.1-deficient double-strain (c-mybhyper;pu.1G242D/G242D) zebrafish to clarify the synergistic role of c-Myb and Pu.1 in promoting MDS/AML development. We found that the c-mybhyper;pu.1G242D/G242D mutant displayed excessive expansion and differentiation arrest of neutrophils, and progressed to MDS/AML with a high ratio. Interestingly, a group of poorly differentiated Pelger-Huët-like neutrophils was identified in c-mybhyper;pu.1G242D/G242D adulthood and might be associated with MDS/AML progression. Moreover, treated the c-mybhyper;pu.1G242D/G242D zebrafish with a combination of the cell cycle inhibitor cytarabine (Ara-C) and the differential inducer all-trans retinoic acid (ATRA) could effectively relieve the leukemic symptoms. Our findings revealed that c-Myb hyperactivation and Pu.1 deficiency synergistically induced MDS/AML. Furthermore, c-mybhyper;pu.1G242D/G242D zebrafish might serve as a suitable MDS/AML model for drug screening.

ORGANISM(S): Danio rerio

PROVIDER: GSE206979 | GEO | 2025/03/19

REPOSITORIES: GEO

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Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.

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The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency in inducing Pelger-Huët anomaly and promoting sAML transformation

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