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

PAX5 Haematolymphoid Tumours (WHO Classification, 5th ed.)

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Primary Author(s)*

Aiko Otsubo Ph.D FACMG

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::HLF fusion

Related Terminology

Acceptable	N/A
Not Recommended	B-lymphoblastic leukaemia/lymphoma with E2A::HLF fusion

Gene Rearrangements

B lymphoblastic leukaemia/lymphoma (B-ALL) with t(17;19)(q22;p13), resulting in the TCF3::HLF gene fusion, is newly recognized as a distinct entity in the WHO 5th edition classification. TCF3 rearrangements are identified in approximately 5–11% of B-ALL cases, with several fusion partners reported, including PBX1, HLF, and ZNF384. B-ALL with TCF3::PBX1 fusion is also classified as a separate entity in the latest WHO edition.

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
TCF3 and HLF	TCF3 (E2A)::HLF	The pathogenic derivative is the der(19) resulting in fusion of 5’ TCF3 and 3’HLF.	t(17;19)(q22;p13)	Rare	D, P	Yes (WHO, NCCN)	This ALL subtype is classified based on the presence of a t(17;19)(q22;p13), which results in fusion of the 5’ portion of TCF3 at “19p13” and the 3’ portion of HLF at “17q22”. The t(17;19) occurs in <1% of childhood B-ALL cases. Although the majority of cases are pediatric, it has also been reported in adults Two major distinct types of TCF3::HLF gene fusion have been identified. Type 1: TCF3 (NM_003200.3) exon 16 fused to HLF (NM_002126.4) exon 4 Type 2: TCF3 exon 15 fused to HLF exon 4 This subtype is characterized by an extremely poor prognosis, high resistance to conventional therapy, and early relapse, and is frequently accompanied by disseminated intravascular coagulation (DIC) and hypercalcemia.

Individual Region Genomic Gain/Loss/LOH

Deletions of PAX5, BTG1, and VPREB1 have been observed in TCF3::HLF-positive B-ALL. Of the 13 reported cases, 8 showed deletions of PAX5. The remaining cases had deletions of BTG1, VPREB1, or both, but not PAX5, indicating deletions of PAX5 are mutually exclusive from deletions of BTG1 and VPREB1. CDKN2A/B deletions have been observed in 3 cases.

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
9	Loss	9p21.3	CDKN2A/B		No	Common recurrent finding in various cancers
9	Loss	9p13	PAX5		No	Common recurrent finding in B-ALL
12	Loss	12q21.33	BTG1		No	Common recurrent finding in B-ALL
22	Loss	22q11.2	VPREB1		No	Common recurrent finding in B-ALL

Characteristic Chromosomal or Other Global Mutational Patterns

Not applicable. (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

Gene Mutations (SNV/INDEL)

RAS pathway gene alterations were identified in several TCF3::HLF-positive B-ALL cases. (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
NRAS	Activating mutations	Oncogene	3/13 cases
KRAS	Activating mutations	Oncogene	3/13 cases
PTPN11	Activating mutations	Oncogene	3/13 cases

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.

Epigenomic Alterations

Not applicable.

Genes and Main Pathways Involved

TCF3 and HLF are both transcription factors, and their fusion generates a chimeric protein that combines the amino-terminal transactivation domains of TCF3 with the carboxy-terminal basic region/leucine zipper DNA-binding and dimerization domain of HLF. The resulting TCF3::HLF fusion protein exhibits altered DNA-binding property compared with wild-type HLF. Functional studies have demonstrated that TCF3::HLF promotes anchorage-independent growth in mouse fibroblast cells and inhibits apoptosis, thereby enhancing cell survival. Gene expression profiling of TCF3::HLF-positive B-ALL cases further revealed extensive transcriptional reprogramming toward an aberrant, immature hematopoietic state. (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
TCF3 and HLF	Lymphoid differentiation	Abnormal gene expression
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

Karyotype, FISH, RT-PCR, DNA or RNA-based NGS

Familial Forms

Not applicable.

Additional Information

Not applicable.

Links

TCF3

HLF

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References

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Notes

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Prior Author(s):

*Citation of this Page: “B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/11/2025, https://ccga.io/index.php/HAEM5:B_lymphoblastic_leukaemia/lymphoma_with_TCF3::HLF_fusion.