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

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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

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 at 19p13 and of 3’HLF at 17p22.	t(17;19)(q22;p13)	Rare (<1% of childhood B-ALL cases)	D, P	Yes (WHO, NCCN)	1% of childhood B-ALL cases. Majority of cases are pediatric, but it has also been reported in adults Two major 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 Extremely poor prognosis, high resistance to conventional therapy, and early relapse Frequently accompanied by disseminated intravascular coagulation (DIC) and hypercalcemia.

TCF3 rearrangements are identified in approximately 5–11% of B-ALL cases. Other fusion partners reported include PBX1 and ZNF384 where B-ALL with TCF3::PBX1 fusion is classified as a separate, distinct entity in the latest WHO edition.

Individual Region Genomic Gain/Loss/LOH

Of 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 were 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	9p13	PAX5	NA	No	Common recurrent finding in B-ALL; may be mutually exclusive from deletions of BTG1 and VPREB1
9	Loss	9p21.3	CDKN2A/B	NA	No	Common recurrent finding in various cancers
12	Loss	12q21.33	BTG1	NA	No	Common recurrent finding in B-ALL; may co-occur with deletion of VPREB1; may be mutually exclusive from deletions of PAX5
22	Loss	22q11.2	VPREB1	NA	No	Common recurrent finding in B-ALL; may co-occur with deletion of BTG1; may be mutually exclusive from deletions of PAX5

Characteristic Chromosomal or Other Global Mutational Patterns

Not applicable.

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
NA	NA	NA	NA	NA	NA

Gene Mutations (SNV/INDEL)

RAS pathway gene alterations were common in TCF3::HLF-positive B-ALL cases.

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	Common	NA	No	Treatment potential with MAPK/MEK inhibitors
KRAS	Activating mutations	Oncogene	Recurrent	NA	No	Treatment potential with MAPK/MEK inhibitors
PTPN11	Gain of function	Oncogene	Recurrent	NA	No	Treatment potential with MAPK/MEK inhibitors

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.

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
TCF3 and HLF; fusion creates chimeric protein	Lymphoid differentiation	Abnormal gene expression leads to stem-like state, anti-apoptotic signaling and differentiation arrest
BCL2; transcriptional upregulation	Anti-apoptosis	Cell survival
NRAS, KRAS, PTPN11; activating mutations	RAS/MAPK pathway	Cell proliferation
CDKN2A/B; deletions	Cell cycle regulation	Cell proliferation

Genetic Diagnostic Testing Methods

Karyotype analysis: fusion may be cryptic

FISH: TCF3 breakapart probe cannot distinguish between TCF3::HLF and TCF3::PBX1

RT-PCR: multiple primers needed to cover alternative fusion variants

DNA or RNA-based NGS: detects all transcript variants

Familial Forms

Not applicable.

Additional Information

Not applicable.

Links

TCF3

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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): Not applicable

*Citation of this Page: Otsubo A. “B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/14/2026, https://ccga.io/index.php/HAEM5:B_lymphoblastic_leukaemia/lymphoma_with_TCF3::HLF_fusion.