B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion
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[1][2]
Two major types of TCF3::HLF gene fusion have been identified[3][4][5].
|
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[10].
Individual Region Genomic Gain/Loss/LOH
Of 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 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[11][12].
| 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[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].
| 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
References
- ↑ Ahmed, Maria Z.; Venkatadasari, Indrani; Dyer, Sara; Wall, Kerry; Huxley, Emma; Lovell, Richard; Kishore, Bhuvan; Dassanayake, Hansini; Francis, Sebastian (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ Zeckanovic, Aida; Mouttet, Brice; Vinti, Luciana; Ancliff, Philip; Brethon, Benoît; Cario, Gunnar; Elitzur, Sarah; Hazar, Volkan; Kunz, Joachim (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. PMID 39911115.
- ↑ Hunger, S. P.; Devaraj, P. E.; Foroni, L.; Secker-Walker, L. M.; Cleary, M. L. (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.
- ↑ Panagopoulos, Ioannis; Micci, Francesca; Thorsen, Jim; Haugom, Lisbeth; Tierens, Anne; Ulvmoen, Aina; Heim, Sverre (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ Lejman, Monika; Włodarczyk, Monika; Zawitkowska, Joanna; Kowalczyk, Jerzy R. (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. PMID 32245383.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ↑ 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.
- ↑ Matsunaga, Takayuki; Inaba, Toshiya; Matsui, Hirotaka; Okuya, Mayuko; Miyajima, Atsushi; Inukai, Takeshi; Funabiki, Tetsunori; Endo, Mikiya; Look, A. Thomas (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.
- ↑ Minson, Katherine A.; Prasad, Pinki; Vear, Susan; Borinstein, Scott; Ho, Richard; Domm, Jennifer; Frangoul, Haydar (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.
{{cite journal}}: CS1 maint: article number as page number (link) CS1 maint: unflagged free DOI (link) - ↑ Inukai, T.; Hirose, K.; Inaba, T.; Kurosawa, H.; Hama, A.; Inada, H.; Chin, M.; Nagatoshi, Y.; Ohtsuka, Y. (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ 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
- ↑ 11.0 11.1 Ma, Xiaotu; Edmonson, Michael; Yergeau, Donald; Muzny, Donna M.; Hampton, Oliver A.; Rusch, Michael; Song, Guangchun; Easton, John; Harvey, Richard C. (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.
- ↑ 12.0 12.1 12.2 Fischer, Ute; Forster, Michael; Rinaldi, Anna; Risch, Thomas; Sungalee, Stéphanie; Warnatz, Hans-Jörg; Bornhauser, Beat; Gombert, Michael; Kratsch, Christina (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ Hunger, S. P.; Ohyashiki, K.; Toyama, K.; Cleary, M. L. (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ Yoshihara, T.; Inaba, T.; Shapiro, L. H.; Kato, J. Y.; Look, A. T. (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ Inukai, T.; Inaba, T.; Yoshihara, T.; Look, A. T. (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.
{{cite journal}}: Check date values in:|date=(help) - ↑ Inaba, T.; Inukai, T.; Yoshihara, T.; Seyschab, H.; Ashmun, R. A.; Canman, C. E.; Laken, S. J.; Kastan, M. B.; Look, A. T. (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.
- ↑ Inukai, T.; Inaba, T.; Ikushima, S.; Look, A. T. (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.
{{cite journal}}: Check date values in:|date=(help)
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.