AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms

Rejeski, Kai; Duque‐Afonso, Jesús; Lübbert, Michael

doi:10.1038/s41388-021-01952-w

Cited by 37 publications

(23 citation statements)

References 137 publications

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“…The addition of capture sequence to the gRNA backbone enabled their detection coincidentally with the single-cell transcriptome and this allowed us to demonstrate that that RUNX1T1 gRNAs were significantly enriched in cells within the expanded arterial cluster. RUNX1T1, also known as ETO, has been associated with the t(8;21) chromosomal translocation that results in the generation of the leukemic fusion protein, AML1/ETO (Rejeski, Duque-Afonso and Lübbert, 2021). RUNX1T1 expression has been recently detected in transcriptomic analysis of the human AGM region (Zeng et al ., 2019; Calvanese et al ., 2022), but its precise role during the ontogeny of the blood system has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Arterial cells support the development of human hematopoietic progenitors in vitro via secretion of IGFBP2

Petazzi

Ventura

May

et al. 2022

Preprint

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Hematopoietic stem and progenitor cells develop from the hemogenic endothelium located in various sites during development, including the dorsal aorta from where Hematopoietic Stem Cells (HSCs) emerge. This process has proven especially challenging to recapitulate in vitro from pluripotent stem cells and further studies are needed to pinpoint the missing stimuli in vitro. Here, we compared iPSC-derived endothelial cells and in vivo HSC-primed hemogenic endothelium and identified 9 transcription factors expressed at significantly lower levels in cells generated in vitro. Using a novel DOX-inducible CRISPR activation system we induced the expression of those genes during in vitro differentiation. To study the phenotypical changes induced by the activation of target genes, we employed single cell RNA sequencing in combination with engineered gRNA that are detectable within the sequencing pipeline. Our data showed a significant expansion of arterial-fated endothelial cells associated with a higher in vitro progenitor activity. The expanded arterial cluster was marked by high expression of IGFBP2 and it was distinct from the hemogenic cluster that showed increased cell cycle progression. We demonstrated that the addition of IGFBP2 to differentiating PSCs resulted in a higher number of functional progenitors, identifying the supporting role of arterial cells play to the emergence of blood progenitors via IGFBP2 paracrine signalling.

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Section: Discussionmentioning

confidence: 99%

Arterial cells support the development of human hematopoietic progenitors in vitro via secretion of IGFBP2

Petazzi

Ventura

May

et al. 2022

Preprint

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“…In AML, aberrant chromosomal translocations can generate gene fusions, producing oncofusion proteins which underpin tumorigenesis. One of the most widely detected oncofusion genes, AML1-ETO (AE), is widely known to be responsible for myeloid leukemogenesis [ 100 , 101 , 102 ]. Shima et al (2019) showed that the AE fusion gene consists of four canonical PASs and favors a shorter length in both t(8;21) AML primary patients and cell lines [ 103 ].…”

Section: 3’ Untranslated Regions (3’utrs) Of Mrnasmentioning

confidence: 99%

Circular RNAs and Untranslated Regions in Acute Myeloid Leukemia

Yeh

Cheong

Tay

2023

IJMS

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Before the advent of next-generation sequencing, research on acute myeloid leukemia (AML) mostly centered on protein-coding genes. In recent years, breakthroughs in RNA sequencing technologies and whole transcriptome analysis have led to the discovery that approximately 97.5% of the human genome is transcribed into non-coding RNAs (ncRNAs). This paradigm shift has led to an explosion of research interest in different classes of non-coding RNAs, such as circular RNAs (circRNAs) as well as non-coding untranslated regions (UTRs) of protein-coding messenger RNAs. The critical roles of circRNAs and UTRs in AML pathogenesis have become increasingly apparent. In this review, we discuss the cellular mechanisms of circRNAs and summarize recent studies that reveal their biological roles in AML. Furthermore, we also review the contribution of 3′UTRs to disease progression. Finally, we discuss the potential of circRNAs and 3′UTRs as new biomarkers for disease stratification and/or the prediction of treatment response and targets for the development of RNA-directed therapeutic applications.

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“…The AML1-ETO protein is viewed as regulating gene expression via epigenetic mechanisms. The fusion protein recruits multiple chromatin-modifying enzymes to target genes, to alter chromatin marks and transcription factor binding ( Rejeski et al, 2021 ). The MLL1 gene that is rearranged in infant B-cell ALL encodes the histone lysine-specific methyltransferase 2A which plays a role in gene expression ( Winters and Bernt, 2017 ).…”

Section: Signature Mutations In Leukemiamentioning

confidence: 99%

Lessons to cancer from studies of leukemia and hematopoiesis

Brown

2022

Front. Cell Dev. Biol.

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The starting point to describing the origin and nature of any cancer must be knowledge about how the normal counterpart tissue develops. New principles to the nature of hematopoietic stem cells have arisen in recent years. In particular, hematopoietic stem cells can “choose” a cell lineage directly from a spectrum of the end-cell options, and are, therefore, a heterogeneous population of lineage affiliated/biased cells. These cells remain versatile because the developmental trajectories of hematopoietic stem and progenitor cells are broad. From studies of human acute myeloid leukemia, leukemia is also a hierarchy of maturing or partially maturing cells that are sustained by leukemia stem cells at the apex. This cellular hierarchy model has been extended to a wide variety of human solid tumors, by the identification of cancer stem cells, and is termed the cancer stem cell model. At least, two genomic insults are needed for cancer, as seen from studies of human childhood acute lymphoblastic leukemia. There are signature mutations for some leukemia’s and some relate to a transcription factor that guides the cell lineage of developing hematopoietic stem/progenitor cells. Similarly, some oncogenes restrict the fate of leukemia stem cells and their offspring to a single maturation pathway. In this case, a loss of intrinsic stem cell versatility seems to be a property of leukemia stem cells. To provide more effective cures for leukemia, there is the need to find ways to eliminate leukemia stem cells.

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AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms

Cited by 37 publications

References 137 publications

Arterial cells support the development of human hematopoietic progenitors in vitro via secretion of IGFBP2

Arterial cells support the development of human hematopoietic progenitors in vitro via secretion of IGFBP2

Circular RNAs and Untranslated Regions in Acute Myeloid Leukemia

Lessons to cancer from studies of leukemia and hematopoiesis

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