HAEM5:B lymphoblastic leukaemia/lymphoma with TCF3::PBX1 fusion

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

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(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). 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

Cancer Category / Type

B-Lymphoblastic Leukemia/Lymphoma

Cancer Sub-Classification / Subtype

B-Lymphoblastic Leukemia/Lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1

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.

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.

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

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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.

Sites of Involvement

Bone marrow, Blood, Central Nervous System (CNS)

Morphologic Features

There are no unique morphological features that distinguish this entity from other types of ALL.

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

editv4:Immunophenotype

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Blasts with pre-B phenotype, positive for CD19, CD10 and cytoplasmic mu heavy chain.

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)

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The breakpoints of the t(1;19) translocation typically fall within intron 16 of TCF3 and intron 3 of PBX1.

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.

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

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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)

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 / Patterns

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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.

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)

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Secondary somatic DNA mutations are not frequently seen in TCF3-PBX1 B-ALL.

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.

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 Involved

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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

Genetic Diagnostic Testing Methods

• Conventional chromosome analysis with FISH confirmation

• RT-PCR
• DNA or RNA based NGS analysis

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.
• 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).

Links

TCF3

PBX1

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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 TCF3::PBX1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:B_lymphoblastic_leukaemia/lymphoma_with_TCF3::PBX1_fusion.