RUNX1

Primary Author(s)*

Brian Davis, PhD

Synonyms

"Runt-related transcription factor 1"; "Acute Myeloid Leukemia 1 Protein"; AML1; ; "Core-Binding Factor Subunit Alpha-2"; CBF2 alpha; CBFA2; "Polyomavirus Enhancer-Binding Protein 2 Alpha B Subunit"; PEBP2aB; PEBP2 alpha; EVI-1; AML1-EVI-1; AMLCR1;

Genomic Location

Cytoband: 21q22.12

Genomic Coordinates:

chr21:36,160,098-37,376,965 [hg19]

chr21:34,787,801-36,004,667 [hg38]

Cancer Category/Type

Acute Myeloid Leukemia (AML)

The frequency of mutations in RUNX1 mutations has been found to be between 5-18% of all Acute Myeloid Leukemia patients tested (3). The most common chromosomal translocations is t(8;21)(q22;q22) (RUNX1-RUNX1T1) in de novo AML, at approximately 7% (2, 6). This translocation confers a favorable prognosis in AML and other neoplasms (2, 5, 6). Other mutations in RUNX1 include deletions, missense, splicing, frameshift, and nonsense mutations (mostly loss of function or decreased function) and occur at a frequency of approximately 10% in AML patients (6). These mutations are mechanistically distinct from the chromosomal translocations and confer a worse prognosis (2, 5, 6)

Acute Lymphocytic Leukemia (ALL)

iAMP21 is an intrachromosomal amplification of Chromosome 21 which includes the genes RUNX1, miR-802 among others. This amplification occurs in about 1.5-2% of all Acute Lymphocytic Leukemia cases tested and is associated with poor prognostication (5).

T-cell Acute Lymphocytic Leukemia (T-ALL) RUNX1 mutations have bee described in 20% o patients with early T-cell precursor acute lymphoblastic leukemia (ETP-ALL)(6).

B-cell Acute Lymphocytic Leukemia (B-ALL)

The most common chromosomal translocations is t(12;21)(p13;q22) (ETV6-RUNX1) in B-cell acute lymphocytic leukemia (B-ALL) (2). This translocation occurs in 25% of Pediatric B-ALL but only 2% of Adult B-ALL (5, 6). This translocation confers a favorable prognosis in B-ALL and other neoplasms (2, 5, 6). iAMP21 is an intrachromosomal amplification of Chromosome 21 which includes the genes RUNX1, miR-802 among others. This amplification occurs in about 2% of all B-cell Acute Lymphocytic Leukemia cases tested and is associated with poor prognostication (6).

Chromic Myeloid Leukemia (CML)

Myelodysplastic Syndrome (MDS)

CCUS or ICUS

RUNX1 mutations are more common in clonal cytopenia of undetermined significance (CCUS) (2)

Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML)

From Wang et al. 2017. RUNX1 mutations are present in 5% to 18% of AML [59–62]. They are associated with ASXL1 [59], MLLPTD [62], and IDH1/IDH2 mutations [62] and are essentially mutually exclusive of NPM1 mutations [59, 62]. RUNX1 mutations were found to be associated with resistance to chemotherapy, inferior DFS, EFS [59, 61, 62], and OS [59–62]. More importantly, RUNX1 mutations were deemed to be an independent prognostic marker for shorter EFS in multivariable analysis [62]. An explorative subgroup analysis demonstrated that RUNX1-mutated AML patients benefited from allo-HSC in terms of RFS [62].

Gene Overview

The protein encoded by RUNX1 can bind the protein encoded by CBFB to form "Core Binding Factor", a hetero-dimeric transcription factor, which regulates a number of genes responsible for hematopoiesis and osteogenesis (2). Runx1 protein can bind to DNA as a monomer through the Runt domain within the Runx1 protein. The RUNX1 gene is the most frequent target for chromosomal translocation in leukemia (1). Alterations of RUNX1 are typically loss of function or decreased function, and are considered "secondary driver mutations" (disease progression) in sporadic leukemias (2), but germline RUNX1 mutations contribute a lifetime risk of myeloid malignancy of about 44% (2). RUNX1 mutations (loss of function or decreased function) have been associated with decreased P53 activity and increased DNA repair defects and increased inflammation (2).

Common Alteration Types

Acute Myeloid Leukemia (AML); t(8;21)(q22;q22) (RUNX1-RUNX1T1)

B-cell Acute Lymphocytic Leukemia (B-ALL); t(12;21)(p13;q22) (ETV6-RUNX1)

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion
			X		X

Internal Pages

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EXAMPLE Germline Cancer Predisposition Genes

External Links

Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.

EXAMPLES

RUNX1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

RUNX1 by COSMIC - sequence information, expression, catalogue of mutations

RUNX1 by CIViC - general knowledge and evidence-based variant specific information

RUNX1 by St. Jude ProteinPaint mutational landscape and matched expression data.

RUNX1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

RUNX1 by Cancer Index - gene, pathway, publication information matched to cancer type

RUNX1 by OncoKB - mutational landscape, mutation effect, variant classification

RUNX1 by NCBI - brief gene overview

RUNX1 by My Cancer Genome - brief gene overview

RUNX1 by UniProt - protein and molecular structure and function

RUNX1 by Pfam - gene and protein structure and function information

RUNX1 by GeneCards - general gene information and summaries

"RUNX1" by VOVD(3) - Leiden Open Variation Database

References

1. Trippier, P. C. (2017). Small molecule inhibitors for acute myeloid leukemia: where is the field heading? Future Med. Chem. 13:1453-1456. PMID 28795593 doi: 10.4155/fmc-2017-0114

2. Bellissimo, D.C. and Speck, N. A. (2017). RUNX1 Mutations in Inherited and Sporadic Leukemia. Front Cell Dev. Biol. 5: 111 PMID 29326930 10.3389/fcell.2017.00111

3. Wang, et al. (2017). Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia. Stem Cells Int. 2017:6962379 PMID 28197208 doi: 10.1155/2017/6962379

4. Kamikubo, Y. (2018). Genetic compensation of RUNX family transcription factors in leukemia. Cancer Sci. (online version ahead of publication). PMID 29883054 doi.org/10.1111/cas.13664.

5. Schafer, E.S. . et al. (2015). Molecular Genetics of Acute Lymphoblastic Leukemia in The Molecular Basis of Cancer, 4th edition. Mendelsohn, J, Howley, PM, Israel, MA, Gray, JW, Thompson, CB. Editors. Elsevier Press: Philadelphia, USA, p395-406.

6. Taylor, J. et al. (2017). Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood. 130:410-423. PMID 28600336 doi: 10.1182/blood-2017-02-734541

Notes

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