Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1); RUNX1-RUNX1T1.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Christine Bryke, MD
Beth Israel Deaconess Medical Center, Boston, MA

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s)	Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

Karyogram showing t(8;21)(q22;q22) translocation. Jennifer Otani, Beth Israel Deaconess Medical Center, Boston, MA

t(8;21)(q22;q22)

FISH RUNX1-RUNX1T1 probe set on metaphase cell with t(8;21)(q22;q22) translocation. Jennifer Otani, Beth Israel Deaconess Medical Center, Boston, MA.

editv4:Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(8;21)(q22;q22.1)	5' RUNX1 / 3'RUNX1T1	der(8)	1- 5% of AML

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Diagnostic:

• The presence of t(8;21)(q22;q22) is diagnostic of a cytogenetic subtype of acute myeloid leukemia with maturation in the neutrophilic lineage.
• When t(8;21)(q22;q22) is present the diagnosis of acute myeloid leukemia is made regardless of a blast count less than 20%.

Prognostic:

• t(8;21)(q22;q22) positive AML usually has a good response to chemotherapy and a high complete remission rate with long-term disease-free survival when treated with high dose cytarabine in the consolidation phase. Factors that appear to adversely affected prognosis include CD56 expression and KIT gene mutations. The prognostic significance of other accompanying gene mutations is under investigation.

Therapeutic target:

• t(8;21)(q22;q22) positive AML currently has no molecular target for drug therapy.
• Standard induction 7 + 3 chemotherapy regimen of cytarabine for 7 days plus an anthracycline or anthracenedione for 3 days. In first complete remission patients younger than 60 years without a KIT mutation are treated with high dose cytarabine consolidation therapy. If a KIT mutation is present, bone marrow transplant is performed in first complete remission.
• Recently homoharringtonine, aclarubicin and cytarabine as the first course of induction therapy has been found to be highly effective for acute myeloid leukemia with t(8;21)(q22;q22).

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH

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9q22 loss

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Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

editv4:Characteristic Chromosomal Aberrations / Patterns

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Additional aberrations in >70% of cases with t(8;21); common loss of a sex chromosome or deletion 9q

Trisomy 4 is a rare numerical abnormality detected in 3% of AML patients with t(8;21) (PMIDs: 12682630, 26573082, 27451976). A negative effect on prognosis this group of patients has been attributed to the presence of the mutations in the KIT gene.. Gain of chromosome 4 would likely result in increased dosage of the mutant KIT allele (PMIDs: 16291592, 30899636).

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Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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AML with t(8;21)(q22;q22) has genetic heterogeneity at the molecular level. Several genes have been identified that are frequently mutated in this subset of AML, some of them adversely affecting prognosis.

• KIT mutations occur in 20-25% of cases and are associated with a high risk of relapse in AML with t(8;21)(q22;q22). Patients with KIT mutations have a significantly shorter overall survival and disease free survival periods than those without KIT mutations.

• In a study of 139 t(8;21)(q22;q22) AML patients were investigated for possible mutations in KIT and 10 other genes (ASXL1, FLT3, NPM1, MLL, IDH1, IDH2, KRAS, NRAS, CBL, and JAK2). 49.6% had one mutation in addition to the t(8;21)(q22;q22). These were most often KIT, NRAS and ASXL1. 16.5% of patients had ≥2 mutations. Infrequent accompanying mutated genes found in only 2.9-5% of cases include in decreasing frequency: FLT3-ITD, FLT3-TKD, CBL, and KRAS, IDH2 and JAK2. These mutations did not adversely affect prognosis. NPM1 mutations are thought to be mutually exclusive of RUNX1-RUNX1T1.

• ASXL2 mutations have been identified in greater than 20% of patients with t(8;21), but not in patients with inv(16)/t(16;16) or RUNX1-mutated AML. ASXL2 mutations are similarly frequent in adults and children with t(8;21) and are mutually exclusive with ASXL1 mutations. Although overall survival is similar between ASXL1 and ASXL2 mutant t(8;21) AML patients and their wild-type counterparts, patients with ASXL1 or ASXL2 mutations had a cumulative incidence of relapse that is significantly higher than with their ASXL1 or ASXL2 wild-type counterparts.

• Recurring ZBTB7A mutations have been identified in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for hematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, it has been shown that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.

• WT1 mutations have been found to be relatively common (13.8%) in core binding factor leukemia. Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation.

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
KIT				20-30%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	NRAS and ASXL1
Secondary Mutations
Mutually Exclusive	ASXL1 and ASXL2

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Epigenomic Alterations

None

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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Genes:

• RUNX1T1 (also known as ETO) on 8q22 is transcribed from telomere to centromere; 3 proline rich domains; 2 zinc finger, and a PEST region in the C-terminus; tissue restricted expression; nuclear localization; putative transcription factor.

• RUNX1 (also known as AML1 and CBFA) on 21q22; contains a runt domain and a transactivation domain in the C-terminus; forms heterodimers; widely expressed; nuclear localization; transcription factor (activator) for various hematopoietic-specific genes.

DNA:

• t(8;21)(q22;q22) results in a 5’RUNX1-3’RUNX1T1 hybrid gene involving fusion of the very 5’ end of the RUNX1T1 gene to RUNX1 in an ~25 kb breakpoint region between exons 5 and 6.

Protein:

• A fusion protein with the N-terminus runt domain (responsible for DNA binding and protein-protein interaction) of RUNX1 fused to the 577 C-terminal residues of RUNX1T1. The reciprocal product is not detected. The fusion protein retains the ability to recognize the RUNX1 consensus DNA binding site (it is a negative dominant competitor with the normal RUNX1) and to dimerize with the CBFβ subunit in the heterodimeric core binding factor. The core binding factor is a transcription factor that plays an essential role in regulation of normal hematopoiesis. It is composed of a DNA-binding CBFα (RUNX1) chain and a non-DNA-binding CBFβ chain. It is likely oncogenic due to altered transcriptional regulation of normal RUNX1 target genes. Animal studies suggest that the fusion proteins alone are not able to induce leukemia and that additional genetic alterations are required for leukemogenic transformation.

Key cellular pathways:

• The normal transcriptional activity of the RUNX1 protein in the core binding factor is affected in a negative manner by the chimeric protein encoded by the RUNX1-RUNX1T1 fusion gene. It has been proposed that the RUNX1-RUNX1T1 protein recruits histone deacetylases and DNA methyl transferase 1 to core binding factor target genes. This leads to increased chromatin deacetylation and promotor hypermethylation, resulting in gene transcriptional repression and disruption of normal cellular pathways of hematopoiesis.

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Genetic Diagnostic Testing Methods

• Chromosome analysis, FISH, RT-PCR
• FISH or RT-PCR is needed for cytogenetically cryptic cases with typical blast morphology and immunophenotype
• RT-PCR is employed for minimal residual disease detection

FISH with RUNX1-RUNX1T1 probe set on interphase cells with t(8;21)(q22;q22) translocation. Nancy Hsu and Min Zhang, Beth Israel Deaconess Medical Center, Boston, MA.

Familial Forms

None

Additional Information

This disease is defined/characterized as detailed below:

Acute myeloid leukemia (AML) with t(8;21)(q22;q22) resulting in RUNX1-RUNX1T1 gene fusion defines a subtype of AML with neutrophil lineage maturation. In the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, it is in the group of AML with recurrent genetic abnormalities. In the older French-American-British (FAB) classification system, t(8;21)(q22;q22) positive AML belonged to the acute myeloblastic leukemia with maturation M2 category and accounted for 10% of cases. t(8;21)(q22;q22) can occasionally be seen in therapy-related AML. In those instances the leukemia is not classified in the group of AML with recurrent genetic abnormalities due to clinical and prognostic differences. AML with t(8;21)(q22;q22) is a core binding leukemia (see Genes and Main Pathways Involved section below).

• t(8;21)(q22;q22) is a translocation involving the long arms of chromosomes 8 and 21 that defines a distinctive cytogenetic subtype of acute myeloid leukemia.
• Complex translocations involving chromosomes 8, 21 and a third chromosome occur; the derivative chromosome 8 in the t(8;21)(q22;q22) and the variant t(8;21;var) carries the RUNX1-RUNX1T1 gene rearrangement.
• Cases with cryptic RUNX1-RUNX1T1 gene rearrangement have been reported.
• Note: The RUNX1T1 gene is currently located at 8q21.3. This gene was previously located at 8q22, which explains the discrepancy in the breakpoint given in the name for this WHO-defined disease entity.

The epidemiology/prevalence of this disease is detailed below:

Approximately 1-5% of AML cases have the t(8;21)(q22;q22.1)

• Occurs mainly in younger patients
• Mean age is 30 years
• Most common type of AML in children

The clinical features of this disease are detailed below:

• May present as a myeloid sarcoma and, if so, the bone marrow aspirate blast count may be misleadingly low
• Concurrent systemic mastocytosis has been reported

The sites of involvement of this disease are detailed below:

• Bone marrow

The morphologic features of this disease are detailed below:

• Large blasts with abundant basophilic cytoplasm often with azurophilic granules and perinuclear clearing
• Long sharp Auer rods are frequently observed.

• Promyelocytes, myelocytes and metamyelocytes may have abnormal nuclear segmentation and cytoplasmic staining.
• Normal eosinophil precursors are frequently increased and do not show the nuclear and cytoplasmic abnormalities seen in AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22).
• Cases with t(8;21)(q22;q22.1) and less than 20% blast percentage in the marrow should be classified as AML rather than myelodysplastic syndrome according to the WHO 2017.

Bone marrow aspirate with t(8;21)(q22;q22) blast with Auer rod (100X). Robert Willim, MD, Beth Israel Deaconess Medical Center, Boston, MA

The immunophenotype of this disease is detailed below:

• Blasts express CD34, HLA-DR, MPO, CD13, CD33 (weak), CD15 and/or CD65, co-expression of CD34. Lymphoid markers: CD19, PAX5, sometimes cytoplasmic CD79a
• Occasional weak TdT positivity and/or CD56 expression may have adverse prognosis

Links

RUNX1

RUNX1T1

KIT mutations in AML COSMIC database

www.uptodate.com cytogenetics in AML
www.genenames.org RUNX1
www.genenames.org RUNX1T1

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

Edited by: Fabiola Quintero-Rivera 7/21/2018

*Citation of this Page: “Acute myeloid leukaemia with RUNX1::RUNX1T1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_RUNX1::RUNX1T1_fusion.