Synergism 1 between RUNX1 and PHF6 mutations in leukemogenesis [scRNAseq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1152906 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:RUNX family transcription factor 1 (RUNX1) mutated acute myeloid leukemia (AML) has now been formally classified as AML with myelodysplasia-related gene mutations, and considered to predict adverse prognosis. In addition, mutations of RUNX1 and plant homeodomain finger gene 6 (PHF6) frequently co-occurred and conferred particularly adverse clinical outcomes. Becasue the pathological effects of these combined mutations remained understudied, we sought to address this topic through genetically modified mouse models. We found that Phf6 knockout and RUNX1 double-mutated bone marrow (BM) cells displayed significantly higher engraftment capacity, and recipient mice transplanted with double-mutated BM cells developed AML with significantly shortened survival. We also discovered that the multipotent progenitors (MPPs) were the main cell subpopulation responsible for double-mutated BM cell-induced leukemia. Our findings highlighted the synergistic leukemogenic potential of Phf6 and RUNX1 mutations in vivo, and provided evidence for possible underlying molecular mechanisms.
2025-08-06 | GSE275754 | GEO
Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
2023-05-10 | PXD030616 | Pride
Project description:To investigate the effect of PHF6 mutations in leukemogenesis, we generated Phf6R274X transgenetic(Tg) and Phf6 KO mice. Then we purified the Lineage-cKit+Sca-1+ cells from bone marrow of Phf6R274XTg, Phf6 KO and WT mice, and performed bulk RNA-seq to profile the transcriptom.
2026-06-01 | GSE198499 | GEO
Project description:PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Our comprehensive genomic analyses focused on three main findings. Firstly, we revealed a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 were co-mutated with PHF6. In contrast, female cases revealed co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis revealed a direct interaction between PHF6 and the pioneer transcription factor RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrated a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival were additive as PHF6MT cases with RUNX1 mutations had worse outcomes when compared to cases carrying single mutation or wild-type.
2023-11-21 | PXD042441 | Pride
Project description: Not available
| S-EPMC12302341 | biostudies-literature
Project description:To investigate the effect of PHF6 mutations in leukemogenesis, we generated Phf6R274X transgenetic(Tg) mice. Then we purified the Lineage-cKit+ cells from bone marrow of Phf6R274XTg and WT mice, and performed single cell RNA-seq to study hematopoietic stem cell differentiation trajectory.
2026-06-01 | GSE198501 | GEO
Project description:To investigate the effect of PHF6 mutations in leukemogenesis, we generated Phf6R274X transgenetic(Tg) mice. Then we purified the cKit+ cells from bone marrow of Phf6R274XTg and WT mice, and performed ChIP-seq to study histone modification in hematopoietic stem and progenitor cells.
2026-06-01 | GSE198500 | GEO
Project description:Deciphering the synergy of RUNX1 with GATA1s mutation in trisomy 21 associated leukemogenesis
| PRJEB43639 | ENA
Project description:The leukemia fusion gene CBFB-MYH11 requires RUNX1 for leukemogenesis, but the underlying mechanism is unclear. By in vitro studies, we found that CBFβ-SMMHC, the chimeric protein encoded by CBFB-MYH11, could enhance the binding affinity between RUNX1 and its target DNA. Increased RUNX1-DNA binding was also observed in myeloid progenitor cells from mice expressing CBFβ-SMMHC. Moreover, only CBFβ-SMMHC variants able to enhance the DNA binding affinity by RUNX1 could induce leukemia in mouse models. Significant transcriptomic changes, affecting genes associated with inflammatory response and target genes of CBFA2T3, were observed in mice expressing leukemogenic CBFβ-SMMHC variants. Finally, we show that CBFβ-SMMHC could not induce leukemia in mice with a Runx1-R188Q mutation, which reduces RUNX1 DNA binding but not affecting its interaction with CBFβ-SMMHC or its sequestration to cytoplasm by CBFβ-SMMHC. Our data suggest that enhancing RUNX1-target DNA binding affinity is an important mechanism of leukemogenesis by CBFβ-SMMHC.
2025-06-23 | GSE285824 | GEO
Project description:Phf6 truncating mutation drives leukemogenesis via disrupted epigenetic regulation in mice
| PRJNA815648 | ENA