Brian Davis, PhD, MindFull Informatics LLC
"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
The frequency of RUNX1 mutations is between 5-18% of all AML patients tested . The most common chromosomal translocation is t(8;21)(q22;q22) resulting in RUNX1-RUNX1T1 fusion in de novo AML, at approximately 7% [2,6]. This translocation confers a favorable prognosis in AML and other neoplasms [2,5,6]. Another RUNX1 alteration is the t(3;21)(q26;q22), in which the RUNT domain of RUNX1 is fused to the entire EVI1 gene. This translocation is rarely found in patients diagnosed with de novo AML and is more common in those with therapy-related myelodysplastic syndrome (MDS)/AML . Other mutations in RUNX1 include deletions, missense, splicing, frameshift, and nonsense alterations (mostly loss-of-function or decreased function), and occur at a frequency of approximately 10% in AML patients . These mutations are mechanistically distinct from the chromosomal translocations and confer a worse prognosis [2,5,6].
iAMP21 is an intrachromosomal amplification of chromosome 21, which includes the genes RUNX1 and 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 .
RUNX1 mutations have been described in 20% of patients with early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) .
The most common chromosomal translocation is t(12;21)(p13;q22) resulting in ETV6-RUNX1 fusion in B-cell acute lymphocytic leukemia (B-ALL) . This translocation occurs in 25% of Pediatric B-ALL but only 2% of Adult B-ALL [5, 6], and 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 and 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 .
- Chronic Myeloid Leukemia (CML)
A number of simple mutations in RUNX1 have been reported in CML patients, and these mutations may be in part responsible for progression from the chronic phase to blast crisis (BC) .
A high frequency (42%) of RUNX1 mutations has been reported among radiation-associated and therapy-related Myelodysplastic Syndrome (MDS) patients .
- CCUS (Clonal cytopenia of undetermined significance) or ICUS (Idiopathic cytopenia of undetermined significance )
RUNX1 mutations are more common in clonal cytopenia of undetermined significance (CCUS) .
- Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML)
Germline mutations of RUNX1 have been reported in the rare autosomal dominant Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) .
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 . Runx1 protein can bind to DNA as a monomer through the Runt domain within the Runx1 protein. RUNX1 is the most frequent target for chromosomal translocation in leukemia . Alterations of RUNX1 are typically loss-of-function or decreased function, and are considered "secondary driver mutations" (disease progression) in sporadic leukemias ; however, germline RUNX1 mutations contribute to a lifetime risk for myeloid malignancy of about 44% . RUNX1 mutations (loss-of-function or decreased function) have been associated with decreased P53 activity and increased DNA repair defects and increased inflammation . RUNX1 mutations are associated with gene mutations in ASXL1, MLLPTD, and IDH1/IDH2, but and are mutually exclusive with NPM1 mutations . Non-complex RUNX1 mutations were found to be associated with resistance to chemotherapy, decreased disease free survival (DFS), event free survival (EFS) and overall survival (OS) .
Common Alteration Types
Acute Myeloid Leukemia (AML); t(8;21)(q22;q22) resulting in RUNX1-RUNX1T1 fusion
B-cell Acute Lymphocytic Leukemia (B-ALL); t(12;21)(p13;q22) resulting in ETV6-RUNX1 fusion
|Copy Number Loss||Copy Number Gain||LOH||Loss-of-Function Mutation||Gain-of-Function Mutation||Translocation/Fusion|
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 Gene - 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 OMIM - compendium of human genes and genetic phenotypes
RUNX1 by LOVD(3) - Leiden Open Variation Database
RUNX1 by TICdb - database of Translocation breakpoints In Cancer
RUNX1 by LOVD3
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2. Bellissimo DC and Speck NA, (2017). RUNX1 mutations in inherited and sporadic leukemia. Front Cell Dev Biol 5:111, PMID 29326930. 10.3389/fcell.2017.00111.
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8. Harada H, et al., (2004). High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 103:2316-2324, PMID 14615365. DOI: 10.1182/blood-2003-09-3074.
9. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140-141.
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