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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
The Runx genes: lineage-specific oncogenes and tumor suppressors
1Molecular Oncology Laboratory, Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow G61 1QH, UK. e.r.cameron@vet.gla.ac.uk
Abstract:
The Runx genes present a challenge to the simple binary classification of cancer genes as oncogenes or tumor suppressors. There is evidence that loss of function of two of the three mammalian Runx genes promotes cancer, but in a highly lineage-restricted manner. In human leukemias, the RUNX1 gene is involved in various chromosomal translocation events that create oncogenic fusion proteins, at least some of which appear to function as dominant-negative inhibitors of the normal gene product. Paradoxically, evidence is mounting that structurally intact Runx genes are also oncogenic when overexpressed. All the three murine genes act as targets for transcriptional activation by retroviral insertional mutagenesis, and the oncogenic potential of Runx2 has been confirmed in transgenic mice. Moreover, the RUNX1 gene is often amplified or overexpressed in cases of acute leukemia. The state of progress in elucidating the oncogenic roles of the Runx genes is the subject of this review, and we draw together recent observations in a tentative model for the effects of Runx deregulation on hematopoietic cell differentiation. We suggest that lineage-specific factors determine the sensitivity to the oncogenic effects of loss or overexpression of Runx factors.
Insights
Runx genes challenge cancer gene classification. Both loss and overexpression of Runx genes can promote cancer, with effects varying by cell type and lineage.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Hematopoiesis
Background:
- Runx genes (Runt-related transcription factors) exhibit complex roles in cancer, defying simple oncogene or tumor suppressor classification.
- Evidence suggests loss of function in some Runx genes promotes cancer in a lineage-restricted manner.
- RUNX1 gene alterations, including translocations creating fusion proteins, are implicated in human leukemias.
Purpose of the Study:
- To review the current understanding of the oncogenic roles of Runx genes.
- To synthesize recent findings on Runx gene deregulation in cancer.
- To propose a model for Runx gene effects on hematopoietic cell differentiation.
Main Methods:
- Review of existing literature on Runx gene function and cancer.
- Analysis of evidence from human leukemias and experimental models (transgenic mice, retroviral insertional mutagenesis).
- Integration of observations to develop a model of Runx deregulation.
Main Results:
- Both loss-of-function and overexpression of Runx genes can be oncogenic.
- RUNX1 is frequently involved in chromosomal translocations in leukemia, forming dominant-negative fusion proteins.
- Runx genes are targets of retroviral insertional mutagenesis, and Runx2 overexpression is oncogenic in transgenic models.
- RUNX1 amplification or overexpression is observed in acute leukemia cases.
Conclusions:
- Runx gene deregulation (both loss and overexpression) contributes to cancer development.
- Lineage-specific factors dictate cellular sensitivity to the oncogenic effects of Runx gene alterations.
- A tentative model is proposed for Runx deregulation impacting hematopoietic cell differentiation.
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