B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion

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

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). 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 in a table, click nearby within the table and select the > symbol that appears. 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)*

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[1].

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[2][3]
  • Two major distinct types of TCF3::HLF gene fusion have been identified[4][5][6].
    • 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[7][8][9][10].

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[11][12], 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)

Put your text here and fill in the table (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
EXAMPLE: TP53KRAS; Variable LOF mutationsKRAS


Activating mutations Oncogene 3/13 cases
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

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 specificity compared with wild-type HLF[13]. Functional studies have demonstrated that TCF3::HLF promotes anchorage-independent growth in mouse fibroblast cells[14][15] and inhibits apoptosis, thereby enhancing cell survival[16][17]. Gene expression profiling of TCF3::HLF-positive B-ALL cases further revealed extensive transcriptional reprogramming toward an aberrant, immature hematopoietic state[12]. (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

Put your text here

Links

TCF3

HLF

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References

  1. ↑ WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours, 5th edition, IARC Press:Lyon, 2024. Online at WHO Classification of Tumours
  2. ↑ Ahmed, Maria Z.; et al. (2022-11). "Clonal evolution in adult TCF3::HLF-positive acute lymphoblastic leukemia undergoing stem cell transplantation". Annals of Hematology. 101 (11): 2553–2554. doi:10.1007/s00277-022-04941-5. ISSN 1432-0584. PMID 35907039 Check |pmid= value (help). Check date values in: |date= (help)
  3. ↑ Zeckanovic, Aida; et al. (2025-06-01). "Update on long-term outcomes of a cohort of patients with TCF3::HLF-positive acute lymphoblastic leukemia treated with blinatumomab and stem cell transplantation". Haematologica. 110 (6): 1373–1378. doi:10.3324/haematol.2024.286111. ISSN 1592-8721. PMC 12130763 Check |pmc= value (help). PMID 39911115 Check |pmid= value (help).
  4. ↑ Hunger, S. P.; et al. (1994-05-15). "Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL". Blood. 83 (10): 2970–2977. ISSN 0006-4971. PMID 8180393.
  5. ↑ Panagopoulos, Ioannis; et al. (2012-12). "A novel TCF3-HLF fusion transcript in acute lymphoblastic leukemia with a t(17;19)(q22;p13)". Cancer Genetics. 205 (12): 669–672. doi:10.1016/j.cancergen.2012.10.004. ISSN 2210-7762. PMID 23181981. Check date values in: |date= (help)
  6. ↑ Lejman, Monika; et al. (2020-04-03). "Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL". BMC medical genomics. 13 (1): 58. doi:10.1186/s12920-020-0709-y. ISSN 1755-8794. PMC 7118981 Check |pmc= value (help). PMID 32245383 Check |pmid= value (help).
  7. ↑ Hunger, S. P. (1996-02-15). "Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis". Blood. 87 (4): 1211–1224. ISSN 0006-4971. PMID 8608207.
  8. ↑ Matsunaga, Takayuki; et al. (2004-04-15). "Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein". Blood. 103 (8): 3185–3191. doi:10.1182/blood-2003-09-3022. ISSN 0006-4971. PMID 15070701.
  9. ↑ Minson, Katherine A.; et al. (2013). "t(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature". Case Reports in Hematology. 2013: 563291. doi:10.1155/2013/563291. ISSN 2090-6560. PMC 3549381. PMID 23346431.
  10. ↑ Inukai, T.; et al. (2007-02). "Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19". Leukemia. 21 (2): 288–296. doi:10.1038/sj.leu.2404496. ISSN 0887-6924. PMID 17183364. Check date values in: |date= (help)
  11. ↑ Ma, Xiaotu; et al. (2015-03-19). "Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia". Nature Communications. 6: 6604. doi:10.1038/ncomms7604. ISSN 2041-1723. PMC 4377644. PMID 25790293.
  12. ↑ 12.0 12.1 Fischer, Ute; et al. (2015-09). "Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options". Nature Genetics. 47 (9): 1020–1029. doi:10.1038/ng.3362. ISSN 1546-1718. PMC 4603357. PMID 26214592. Check date values in: |date= (help)
  13. ↑ Hunger, S. P.; et al. (1992-09). "Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia". Genes & Development. 6 (9): 1608–1620. doi:10.1101/gad.6.9.1608. ISSN 0890-9369. PMID 1516826. Check date values in: |date= (help)
  14. ↑ Yoshihara, T.; et al. (1995-06). "E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF". Molecular and Cellular Biology. 15 (6): 3247–3255. doi:10.1128/MCB.15.6.3247. ISSN 0270-7306. PMC 230557. PMID 7760820. Check date values in: |date= (help)
  15. ↑ Inukai, T.; et al. (1997-03). "Cell transformation mediated by homodimeric E2A-HLF transcription factors". Molecular and Cellular Biology. 17 (3): 1417–1424. doi:10.1128/MCB.17.3.1417. ISSN 0270-7306. PMC 231866. PMID 9032268. Check date values in: |date= (help)
  16. ↑ Inaba, T.; et al. (1996-08-08). "Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor". Nature. 382 (6591): 541–544. doi:10.1038/382541a0. ISSN 0028-0836. PMID 8700228.
  17. ↑ Inukai, T.; et al. (1998-10). "The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF". Molecular and Cellular Biology. 18 (10): 6035–6043. doi:10.1128/MCB.18.10.6035. ISSN 0270-7306. PMC 109189. PMID 9742120. Check date values in: |date= (help)

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Notes

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*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.

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