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The runx genes: gain or loss of function in cancer

Key Points

  • The RUNX genes encode transcription factors that bind DNA as components of the core-binding factor (CBF) complex, in partnership with the CBFβ cofactor. This complex activates and represses transcription of key regulators of growth, survival and differentiation pathways.

  • The mouse RUNX genes are closely related and are essential for haematopoiesis, osteogenesis and neurogenesis, but are also important for other developmental processes.

  • The RUNX genes have been found to function as both tumour suppressors and dominant oncogenes in a context-dependent manner.

  • RUNX1 is a frequent target of chromosomal translocation in distinct subtypes of human leukaemia: RUNX1–ETO occurs in 10–20% of acute myeloid leukaemias and TEL–RUNX1 in 20–25% of childhood acute lymphoid leukaemias.

  • Functional disruption of RUNX1 by chromosomal translocation and somatic point mutation occurs commonly in myeloid leukaemia. RUNX1 mutations have also been linked with familial predisposition to acute leukaemia.

  • Hypermethylation of RUNX3 has been found in several human epithelial cancers and loss of Runx3 predisposes knockout mice to gastric hyperplasia, indicating a tumour-suppressor-like role for this gene.

  • All three RUNX genes are targets for retroviral insertional activation in mouse lymphoma models, and transgenic mice expressing full-length Runx2 develop T-cell lymphoma, confirming the oncogenic potential of this gene family.

  • Amplification of RUNX1 has been linked with poor prognosis in childhood B-cell leukaemia, while RUNX2 expression has been implicated in bone metastasis.

  • RUNX proteins are central to pathways regulating cell growth and differentiation. Of particular note are the interactions of RUNX activities with the transforming growth factor-β pathway.

Abstract

The RUNX genes have come to prominence recently because of their roles as essential regulators of cell fate in development and their paradoxical effects in cancer, in which they can function either as tumour-suppressor genes or dominant oncogenes according to context. How can this family of transcription factors have such an ambiguous role in cancer? How and where do these genes impinge on the pathways that regulate growth control and differentiation? And what is the evidence for a wider role for the RUNX genes in non-haematopoietic cancers?

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Figure 1: The structure of the RUNX proteins and their derivatives formed by chromosomal translocations.
Figure 2: RUNX factors as organizers of transcription.
Figure 3: RUNX–CBFB complex genes in cancer.
Figure 4: RUNX–CBF complexes in the determination of cell fate.

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Acknowledgements

We wish to thank colleagues in the Molecular Oncology Laboratory for constructive discussions and critical reading of the manuscript. We apologise in advance to those investigators whose research or contributions to the field was not cited on the basis of space constraints or oversight. The Molecular Oncology Laboratory is supported by a joint programme grant funded by the Leukaemia Research Fund of Great Britain and Cancer Research UK.

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Correspondence to James C. Neil.

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DATABASES

Entrez Gene

CBFβ

CDKN1A

CDKN2A

ETO

EVI1

MYH11

RUNX1

RUNX2

RUNX3

TEL

TGFβ

National Cancer Institute

acute lymphoblastic leukaemia

acute myeloid leukaemia

breast cancer

prostate cancer

OMIM

familial platelet disorder

FURTHER INFORMATION

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Mouse Retroviral Tagged Cancer Gene Database

Glossary

EXON SKIPPING

Exclusion of an exon that is normally included in the mRNA.

HAPLOINSUFFICIENCY

A situation in which a loss-of-function phenotype is produced by mutating one allele of a gene in a diploid cell, even though the other allele is wild type.

MYELODYSPLASTIC SYNDROME

A heterogeneous group of closely related clonal haematopoietic disorders characterized by impaired blood-cell production in the bone marrow. These are chronic preleukaemic conditions that progress to acute myeloid leukaemia in a minority of patients.

FRENCH–AMERICAN–BRITISH SUBTYPES

The French–American–British classification system subdivides acute myeloid leukaemia into eight subtypes based on the stage of differentiation of blasts. M0 subtype represents the most immature cell type, M2 has a mature myeloblastic phenotype, M4Eo is myelomonocytic with eosinophila, and M7 refers to a megakaryoblastic phenotype.

HEMIZYGOUS

A diploid genotype that has only one copy of a particular gene, as in X-chromosome genes in a male, or when the homologous chromosome carries a deletion.

LYMPHOID-SPECIFIC RECOMBINASE

Proteins required for the somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T-cell and B-cell receptors.

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Blyth, K., Cameron, E. & Neil, J. The runx genes: gain or loss of function in cancer. Nat Rev Cancer 5, 376–387 (2005). https://doi.org/10.1038/nrc1607

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