Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression

Zhang, Wenwen; Ma, Qian; Liang, Bing; Sun, Ziqi; Liu, Lingling; Lin, Dongjun; Zhao, Minyi

doi:10.3389/fonc.2021.725336

Cited by 7 publications

(8 citation statements)

References 36 publications

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“…RUNX3 KD did not impact on cell growth. This is in contrast to a recent study that showed that RUNX3 KD inhibits AML progression in MLL::AF9 mice by inducing DNA damage and apoptosis [ 39 ]. Overall, RUNX3 KD did not affect the normal program of myeloid differentiation of human HSPC or AML cell growth, with the caveat that RUNX3 was not completely suppressed.…”

Section: Discussioncontrasting

confidence: 98%

“…Nonetheless, survival analysis of non-CBF AML patients suggests that high RUNX3 levels remain associated with poor outcome. These findings support a recent study that identified RUNX3 as one of three super-enhancer associated genes that is abnormally overexpressed in AML cells compared to normal hematopoietic cells, such as neutrophils, monocytes, and HSPC [ 39 ]. In childhood AML, increased RUNX3 expression was associated with a shortened EFS and OS among patients [ 4 , 40 ].…”

Section: Discussionsupporting

confidence: 90%

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Increased expression of RUNX3 inhibits normal human myeloid development

et al. 2022

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RUNX3 is a transcription factor dysregulated in acute myeloid leukemia (AML). However, its role in normal myeloid development and leukemia is poorly understood. Here we investigate RUNX3 expression in both settings and the impact of its dysregulation on myelopoiesis. We found that RUNX3 mRNA expression was stable during hematopoiesis but decreased with granulocytic differentiation. In AML, RUNX3 mRNA was overexpressed in many disease subtypes, but downregulated in AML with core binding factor abnormalities, such as RUNX1::ETO. Overexpression of RUNX3 in human hematopoietic stem and progenitor cells (HSPC) inhibited myeloid differentiation, particularly of the granulocytic lineage. Proliferation and myeloid colony formation were also inhibited. Conversely, RUNX3 knockdown did not impact the myeloid growth and development of human HSPC. Overexpression of RUNX3 in the context of RUNX1::ETO did not rescue the RUNX1::ETO-mediated block in differentiation. RNA-sequencing showed that RUNX3 overexpression downregulates key developmental genes, such as KIT and RUNX1, while upregulating lymphoid genes, such as KLRB1 and TBX21. Overall, these data show that increased RUNX3 expression observed in AML could contribute to the developmental arrest characteristic of this disease, possibly by driving a competing transcriptional program favoring a lymphoid fate.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionsupporting

confidence: 90%

Increased expression of RUNX3 inhibits normal human myeloid development

et al. 2022

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“…The common TFs shared by SMGR’ and SOMatic's program, such as RUNX1 ( 43 ) and NFE2 ( 44 , 45 ), are known TFs that play important roles in leukemia. Meanwhile, some TFs which are known to be important in acute leukemia can only be identified by the SMGR’s program but not by SOMatic, for example, RUNX3 ( 46 , 47 ), SNAI1 ( 48 ) and THAP1 ( 49 ). Of note, SMGR reveals more regulators based on the co-regulatory program, suggesting the validity and superior performance of SMGR.…”

Section: Resultsmentioning

confidence: 99%

SMGR: a joint statistical method for integrative analysis of single-cell multi-omics data

Song

Zhu

Jin

et al. 2022

NAR Genomics and Bioinformatics

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Unravelling the regulatory programs from single-cell multi-omics data has long been one of the major challenges in genomics, especially in the current emerging single-cell field. Currently there is a huge gap between fast-growing single-cell multi-omics data and effective methods for the integrative analysis of these inherent sparse and heterogeneous data. In this study, we have developed a novel method, Single-cell Multi-omics Gene co-Regulatory algorithm (SMGR), to detect coherent functional regulatory signals and target genes from the joint single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) data obtained from different samples. Given that scRNA-seq and scATAC-seq data can be captured by zero-inflated Negative Binomial distribution, we utilize a generalized linear regression model to identify the latent representation of consistently expressed genes and peaks, thus enables the identification of co-regulatory programs and the elucidation of regulating mechanisms. Results from both simulation and experimental data demonstrate that SMGR outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of SMGR, we apply SMGR to mixed-phenotype acute leukemia (MPAL) and identify the MPAL-specific regulatory program with significant peak-gene links, which greatly enhance our understanding of the regulatory mechanisms and potential targets of this complex tumor.

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“…As a transcription factor, RUNX3 is bound to the promoter of cell cycle-related genes in both normal and AML cells. However, within AML cells, RUNX3 is also bound to the promoters of DNA repair genes ( CHEK1 , RAD51C , RPA2 , and DDB1 ), antiapoptotic genes ( BCL2 , BCL2L10 , BCL2L12 , and MCL1 ), and genes implicated in leukemogenesis ( MYC , CD93 , KIT , IKZF2 , FTO , and SOX4 ) [ 61 ] ( Figure 3 ). In this study, RUNX3 knockdown inhibited leukemic progression by inducing DNA damage and higher apoptosis.…”

Section: Runx3 Defects In Human Cancers and Genomic Instabilitymentioning

confidence: 99%

The RUNX Family of Proteins, DNA Repair, and Cancer

Krishnan

2023

Cells

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The RUNX family of transcription factors, including RUNX1, RUNX2, and RUNX3, are key regulators of development and can function as either tumor suppressors or oncogenes in cancer. Emerging evidence suggests that the dysregulation of RUNX genes can promote genomic instability in both leukemia and solid cancers by impairing DNA repair mechanisms. RUNX proteins control the cellular response to DNA damage by regulating the p53, Fanconi anemia, and oxidative stress repair pathways through transcriptional or non-transcriptional mechanisms. This review highlights the importance of RUNX-dependent DNA repair regulation in human cancers.

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Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression

Cited by 7 publications

References 36 publications

Increased expression of RUNX3 inhibits normal human myeloid development

Increased expression of RUNX3 inhibits normal human myeloid development

SMGR: a joint statistical method for integrative analysis of single-cell multi-omics data

The RUNX Family of Proteins, DNA Repair, and Cancer

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