RUNX1 overexpression triggers TGF-β signaling to upregulate p15 and thereby blocks early hematopoiesis by inducing cell cycle arrest

Yi, Danying; Zhu, Lijiao; Zeng, Jiahui; Liu, Yuanling; Chang, Jing; Zhang, Yonggang; Dong, Yong; Xu, Pan; Chen, Yijin; Zhou, Yifeng; Lai, Mowen; Zhou, Qi; Liu, Jiaxin; Chen, Bin; Ma, Feng

doi:10.1016/j.scr.2022.102694

Cited by 4 publications

(6 citation statements)

References 43 publications

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“…What is more interesting is that while PLCG1 expression is crucial for AML1-ETO LSCs, it is not apparently necessary for calcium specific downstream signaling in normal HSCs [20]. PLCG1 activation is apparent in most leukemia cases and its expression has been linked with chemotherapy resistance where 50% of cases eventually relapse or are diagnosed with a residual disease that affects them for years [21]. Having many signaling pathways influenced by the AML1-ETO complex it proves tricky when finding a general treatment but focusing on specific pathways can allow targeted therapeutic approaches to help alleviate some symptoms of AML.…”

Section: Transcriptional Dysregulation and Different Transcriptional ...mentioning

confidence: 99%

“…AML1 is a transcriptional factor that plays a crucial role in the regulation of hematopoietic differentiation, and it does so through different mechanisms of epigenetic modifications which are reversible modifications that are imposed on a cell's DNA or histones and alter gene expression without changing the initial DNA sequence of the organism [21]. Different modes of epigenetic modifications include DNA methylation, histone de/acetylation, and the activity of noncoding RNA.…”

Section: Epigenetic Modification Discrepancies Between Wild Type Aml1...mentioning

confidence: 99%

“…It was also important to understand how epigenetic modifications are induced by the AML1-ETO transcription factor and how it affects histone and DNA activity leading to AML. AML1 is a transcription factor that induces epigenetic modification via DNA methylation and histone modifications including de/acetylation, as discussed above [21]. The unfused AML1 gene contains an EID domain which facilitates the recruitment of histone acetyltransferase P300 or CREBBP [22].…”

Section: Future Implications and Therapeutic Approaches For Runx1/run...mentioning

confidence: 99%

“…Studies have shown that downregulated CD48 which is common in those with AML, lower NK immune surveillance [7]. Since CD48 mediates acetylation which is a form of epigenetics, it shows us that epigenetic drugs and treatments that target epigenetics, can provide therapeutic effects, and prevent AML immune escape, and should therefore be an area of research that should be researched in the future [21].…”

Section: Future Implications and Therapeutic Approaches For Runx1/run...mentioning

confidence: 99%

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Mechanisms of AML1-ETO Induced Transcription Factor Dysregulation, Epigenetic Modification, and Immune System Evasion in Pre-Leukemic Stem Cells

Kaveen Thanaraj,

Busanelli

2024

URNCST Journal

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Introduction: Acute myeloid leukemia is a cancer of the bone marrow with a low survival rate of 15% among elderly individuals due to its rapid progression and lack of available treatment. Understanding different transcription factors that may contribute to the progression of leukemia and leukemogenesis is crucial in developing effective treatment plans to control the advancement of AML within patients. This paper aims to conduct a literature review where primary articles contain evidence exhibiting a link between transcriptional dysregulation in genes that code for regulatory proteins involved in cell cycle progression and irregularity present in pre-leukemic stem cells. Methods: Databases Medline and Embase were searched using keywords "leukemogenesis," "pre-leukemic," "AML1", "Acute myeloid leukemia", and "AML-ETO". Only studies written in the English language that were published in peerreviewed journals and human post-mortem/pathophysiological studies were considered in the review. The search emphasized studies published between 1998-2023 to include recent literature reported in the respective field. Results: AML1 regulates the expression of cell cycle checkpoint regulating proteins and proteins involved in hematopoietic differentiation in order to prevent asymmetric production of mutated hematopoietic stem cells (HSCs) as well as defective cells from progressing through the cycle via apoptosis. Chromosomal translocations allow for the AML1 gene to be fused with ETO, causing issues with transcriptional regulation, which work to continuously repress the function of this complex, preventing the transcription of necessary proteins needed to regulate the cell cycle. Implications: The fusion of AML1 and ETO causes the deregulation of the transcription complex, repressing the binding of transcription factors. This means that defective cells within hematopoiesis are not subject to apoptosis, leading to the production of pre-leukemic stem cells, which contributes to leukemogenesis. Understanding the mechanisms leading to the production of pre-leukemic stem cells opens up possible treatment channels from pharmacological and physiological approaches. In addition, leukemia can be identified and diagnosed at an earlier stage by identifying AML1 in relation to ETO as a precursor for AML.

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Section: Transcriptional Dysregulation and Different Transcriptional ...mentioning

confidence: 99%

Section: Epigenetic Modification Discrepancies Between Wild Type Aml1...mentioning

confidence: 99%

Section: Future Implications and Therapeutic Approaches For Runx1/run...mentioning

confidence: 99%

Section: Future Implications and Therapeutic Approaches For Runx1/run...mentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of AML1-ETO Induced Transcription Factor Dysregulation, Epigenetic Modification, and Immune System Evasion in Pre-Leukemic Stem Cells

Kaveen Thanaraj,

Busanelli

2024

URNCST Journal

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“…For example, inhibition of RUNX1 in fibroblasts decreased the expression of Ki67 and α-SMA, which are proliferation and fibroblast trans-differentiation markers, respectively. RUNX1 overexpression activates the TGF-β signaling pathway and promotes the expression of p15, resulting in cell cycle arrest (Sun et al, 2022). The interactive effect between RUNX1 and TGF-β may create a vicious circle and facilitate the differentiation of fibroblasts and collagen deposition during the development of lung fibrosis.…”

Section: Signaling Crosstalk Between Runx1 and Pathways Involved In P...mentioning

confidence: 99%

Transcriptional factor RUNX1: A potential therapeutic target for fibrotic pulmonary disease

LIU¹,

WANG²,

Yuan³

et al. 2023

Biocell

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Runt-related transcription factor-1 (RUNX1), also known as the core-binding factor alpha 2 subunit, is closely related to human leukemia. The functions of RUNX1 in modulating cell proliferation, differentiation, and survival in multiple systems have been gradually discovered with the emergence of transgenic mice. RUNX1 is a powerful transcription factor implicated in diverse signaling pathways and cellular mechanisms that participate in lung development and pulmonary diseases. RUNX1 has recently been identified as a target regulator of fibrotic remodeling diseases, particularly in the kidney. However, the role of RUNX1 in pulmonary fibrosis is unclear. Pulmonary fibrosis is characterized by obscure nosogenesis, limited therapy, and poor prognosis. Moreover, the population of patients with pulmonary fibrosis is gradually increasing. Thus, there is an unmet need for therapeutic targets. In this review, we retrospectively discuss the alteration in RUNX1 mRNA expression in the RNA sequencing data of human fibrotic lungs and the protein levels in mouse pulmonary fibrosis. Subsequently, we focused on the interaction between RUNX1 and several signaling pathways involved in pulmonary fibrosis. Finally, this review highlights the therapeutic potential of RUNX1 as a target for slowing the progression of fibrotic lung disease.

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ADA2 regulates inflammation and hematopoietic stem cell emergence via the A2bR pathway in zebrafish

Brix,

Belleri,

Pezzotta

et al. 2024

Commun Biol

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Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients.

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RUNX1 overexpression triggers TGF-β signaling to upregulate p15 and thereby blocks early hematopoiesis by inducing cell cycle arrest

Cited by 4 publications

References 43 publications

Mechanisms of AML1-ETO Induced Transcription Factor Dysregulation, Epigenetic Modification, and Immune System Evasion in Pre-Leukemic Stem Cells

Mechanisms of AML1-ETO Induced Transcription Factor Dysregulation, Epigenetic Modification, and Immune System Evasion in Pre-Leukemic Stem Cells

Transcriptional factor RUNX1: A potential therapeutic target for fibrotic pulmonary disease

ADA2 regulates inflammation and hematopoietic stem cell emergence via the A2bR pathway in zebrafish

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