HAEM4Backup:B-Lymphoblastic Leukemia/Lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1

Primary Author(s)*

Marilena Melas, PhD; Yassmine Akkari, PhD, FACMG

Cancer Category/Type

B-Lymphoblastic Leukemia/Lymphoma

Cancer Sub-Classification / Subtype

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

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

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)

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

Characteristic Chromosomal Aberrations / Patterns

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Genomic Gain/Loss/LOH

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

Gene Mutations (SNV/INDEL)

Put your text here and/or fill in the tables

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53	EXAMPLE R273H	EXAMPLE Tumor Suppressor	EXAMPLE LOF	EXAMPLE 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE IDH1 R123H
Secondary Mutations	EXAMPLE Trisomy 7
Mutually Exclusive	EXAMPLE EGFR Amplification

Epigenomics (Methylation)

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Genes and Main Pathways Involved

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Diagnostic Testing Methods

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

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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.

Familial Forms

Family predisposition ?

Other Information

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Links

ETV6

RUNX1

Put your links here (use "Link" icon at top of page)

References

(use "Cite" icon at top of page)

EXAMPLE Book

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

Notes

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