B lymphoblastic leukaemia/lymphoma with TCF3::PBX1 fusion
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis 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(1;19)(q23;p13.3); TCF3-PBX1.
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. 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 to a table, click within the table and select the > symbol that appears to be given options. 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)*
Binu Porath, PhD. Vanderbilt University Medical Center, Nashville, TN
Linda D. Cooley, MD, MBA. Children's Mercy Kansas City, Kansas City, MO
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 TCF3::PBX1 fusion |
Definition / Description of Disease
Neoplasm of B-cell lineage precursor lymphoblasts where the blasts contain a translocation between PBX1 at 1q23 and TCF3 at 19p13.3.[1]
Synonyms / Terminology
TCF3 is also known as E2A.
Epidemiology / Prevalence
The t(1;19) translocation is present in ~5% pediatric and ~3% adult B-ALL cases. The incidence of this translocation does not vary significantly with age, however, there is a high incidence (~12%) of this rearrangement in African-American children with B-ALL.[2]
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 FeaturesThe content below was from the old template. Please incorporate above.No unique clinical features that distinguish this entity from other types of B-ALL. Common clinical features of B-ALL include:
- Fatigue
- Infections
- Easy bruising/bleeding
Other symptoms present may include:
- Achiness
- Fever
- Night sweats
- Weight loss
These features manifest clinically as anemia, neutropenia, and/or thrombocytopenia. [2]
Sites of Involvement
Bone marrow, Blood, Central Nervous System (CNS) [2]
Morphologic Features
There are no unique morphological features that distinguish this entity from other types of ALL.[1]
Immunophenotype
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| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE: CD1 |
| Positive (subset) | EXAMPLE: CD2 |
| Negative (universal) | EXAMPLE: CD3 |
| Negative (subset) | EXAMPLE: CD4 |
editv4:ImmunophenotypeThe content below was from the old template. Please incorporate above.Blasts with pre-B phenotype, positive for CD19, CD10 and cytoplasmic mu heavy chain. [1]
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.The breakpoints of the t(1;19) translocation typically fall within intron 16 of TCF3 and intron 3 of PBX1. [2]
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence t(1;19)(q23;p13.3) TCF3-PBX1 der(19) More common (75%) t(1;19)(q23;p13.3) TCF3-PBX1 Balanced translocation Less common
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)
The t(1;19) diagnosis was associated with high risk and poor prognosis in earlier studies, however, modern intensive chemotherapy has changed this paradigm. A recent (2021) study showed that patients with TCF3-PBX1 had intermediate rates of 5-year event-free survival (80-88.2%). Despite the favorable prognosis of this subtype of ALL, there is an increased relative risk of central nervous system relapse associated with this translocation. [1][2][3]
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/LOHThe content below was from the old template. Please incorporate above.Secondary somatic copy number aberrations are not frequently seen in TCF3-PBX1 B-ALL
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: 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. Do not delete table.)
| 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). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.The t(1;19) translocation can be balanced or unbalanced. The unbalanced form has a der(19) resulting in trisomy of 1q distal to PBX1.[4]
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.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.Secondary somatic DNA mutations are not frequently seen in TCF3-PBX1 B-ALL. [2]
Other Mutations
Secondary somatic copy number aberrations and DNA mutations are not frequently seen in TCF3-PBX1 B-ALL, commonly found additional abnormalities are listed below. [2][4]
Type Gene/Region/Other Additional abnormalities dup(1q), del(6q), +8, i(9q), i(17q), +21
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 |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.TCF3 gene at 19p13.3 is important during early lymphocyte development, whereas PBX1 at 1q23 is a component of a transcriptional complex that regulates embryogenesis and hematopoiesis. Fusion protein resulting from the TCF3-PBX1 translocation is a transcriptional activator which likely interferes with the normal function of these genes. Expression of this fusion protein is thought to interfere with key regulatory pathways such as WNT and apoptosis/cell cycle control pathways which may drive a leukemic process. The DNA-binding and protein dimerization domains of PBX1 replaces the TCF3 helix-loop-helix DNA-binding motif in TCF3-PBX1 fusion. The remaining transcriptional activating domains of TCF3 leads to constitutive nuclear localization and transformation of PBX1 into an oncogenic transcriptional factor [5][1][2]
Genetic Diagnostic Testing Methods
- Conventional chromosome analysis with FISH confirmation
- RT-PCR
- DNA or RNA based NGS analysis [2]
Familial Forms
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Additional Information
- Another translocation involving the TCF3 gene is t(17;19) which results in the fusion of HLF at 17q22 with TCF3. This variant translocation has been reported in approximately 1% of pediatric B-ALL patients and is associated with a poor prognosis. [1][4]
- A karyotypically identical t(1;19) has been observed in a subset of B-ALL cases, especially in hyperdiploid B-ALL. This translocation does not involve TCF3 or PBX1. Therefore, a FISH confirmation is often necessary to determine the nature of t(1;19). [1][2]
Links
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References
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- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon 2017
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Akkari, Yassmine M. N.; et al. (05 2020). "Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia". Cancer Genetics. 243: 52–72. doi:10.1016/j.cancergen.2020.03.001. ISSN 2210-7762. PMID 32302940 Check
|pmid=value (help). Check date values in:|date=(help) - ↑ Jeha, Sima; et al. (2021-07). "Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy". Blood Cancer Discovery. 2 (4): 326–337. doi:10.1158/2643-3230.bcd-20-0229. ISSN 2643-3249. PMC 8265990 Check
|pmc=value (help). PMID 34250504 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 4.0 4.1 4.2 Meloni-Ehrig A., (2013). The principles of clinical cytogenetics. 3rd edition. Steven L. Gersen and Martha B. Keagle , Editors. Springer. DOI 10.1007/978-1-4419-1688-4. p327-329.
- ↑ Diakos, Christofer; et al. (2014). "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein". PloS One. 9 (2): e87602. doi:10.1371/journal.pone.0087602. ISSN 1932-6203. PMC 3913655. PMID 24503810.
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 TCF3::PBX1 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_TCF3::PBX1_fusion.