HAEM5:B lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 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:B-Lymphoblastic Leukemia/Lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.

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Primary Author(s)*

Marilena Melas, PhD; Yassmine Akkari, PhD, FACMG

Cancer Category/Type

B-Lymphoblastic Leukemia/Lymphoma

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Precursor B-cell neoplasms
Type	B-lymphoblastic leukaemias/lymphomas
Subtype(s)	B lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 fusion

Definition / Description of Disease

• 20 - 30% of childhood preB ALL; most common translocation (Chin Med J (Engl) 2003;116:1298) but not infants; also 3% of adult
• Excellent prognosis due to good response to chemotherapy; 90% remissions; relapses occur later than other ALL

Mihova D. B lymphoblastic leukemia / lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/leukemiapreBALLt1221.html. Accessed June 14th, 2020.

Synonyms / Terminology

B- Lymphoblastic Leukemia (B-ALL) is also known as Precursor B-Cell Lymphoblastic Leukemia, B-Cell...The t(12;21)(p13.2;q22.2) results in the in-frame fusion of the amino terminus of ETV6 (formally known as TEL ) with all known functional domains of RUNX1 (formally known as AML1)

Epidemiology / Prevalence

The t(12;21)(p13.2;q22.2) resulting in the ETV6-RUNX1 fusion is the most common chromosomal rearrangement in pediatric B-ALL present in ~25% of patients diagnosed between the ages of 2 and 10 years. The t(12;21) is less prevalent in adult B-ALL with an estimated incidence of ~3%

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

The content below was from the old template. Please incorporate above.

The presence of ETV6-RUNX1 alters differentiation and enhances self renewal of hematopoietic progenitor cells, particularly of B-lineage. The expression of ETV6-RUNX1 in human cord blood progenitor cells reportedly caused the expansion of a candidate pre-leukemic population that had a growth advantage in the presence of transforming growth factor-β

Sites of Involvement

bone marrow

Morphologic Features

No distinct morphologic features

Immunophenotype

Finding	Marker
Positive (universal)	CD10, CD19, CD34
Positive (subset)	CD3, CD33
Negative (universal)	CD9
Negative (subset)	CD20

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	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).

editv4:Chromosomal Rearrangements (Gene Fusions)

The content below was from the old template. Please incorporate above.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(12;21)(p13.2;q22.1)	ETV6-RUNX1	der(21)t(12;21)	25% of B-ALL cases

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)

ETV6-RUNX1-positive ALL cells have distinct biologic features and are reported to have an increased in vitro sensitivity to anti-leukemic drugs such as L-asparaginase, doxorubicin, etoposide and dexamethasone compared with leukemic cells of other cytogenetic subtypes. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies.Moreover, relapses tend to occur late and have a better salvage rate than other ALL subtypes. A COG (Children's Oncology Group) study indicated that the presence of ETV6-RUNX1 was an independent predictor of favorable outcome.However, in a study from the (DFCI) Dana Farber Cancer Institute Consortium, ETV6-RUNX1 status was not an independent prognostic factor after accounting for age, initial leukocyte count and treatment group.Thus, it is not clear whether the ETV6-RUNX1 fusion has independent prognostic significance in the context of current risk-adapted therapy and whether the outcome of children with ETV6-RUNX1-positive ALL can be further improved by contemporary therapeutic strategies.

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	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 reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

The content below was from the old template. Please incorporate above.

The 12p13 deletion is the most common accompanying abnormality found in approximately 40% of cases resulting in the loss of ETV6 on the chromosome not involved in the rearrangement. In addition, deletion of the CDKN2A/B locus on 9p21 or the PAX5 gene at 9p13 can be both seen in about a quarter of patients [29–32] . These abnormalities, as well as loss of 6q and gain of chromosome 16, are thought to be among the earliest genomic aberrations in t(12;21) positive B-ALL

Chromosome Number	Gain/Loss/Amp/LOH	Region
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:0-1000000
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:0-1000000

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

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Genes and Main Pathways Involved

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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

Genetic Diagnostic Testing Methods

FISH (dual and extra signal), RT-PCR. Since this translocation is cryptic, conventional chromosome analysis would not detect it.

Familial Forms

Family predisposition ?

Additional Information

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Links

ETV6

RUNX1

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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. *Citation of this Page: “B lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:B_lymphoblastic_leukaemia/lymphoma_with_ETV6::RUNX1_fusion.