HAEM5:B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion: Difference between revisions

Aiko Otsubo, Ph.D. FACMG

|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)

|''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)

|Yes (WHO, NCCN)

|1% of childhood B-ALL cases. Majority of cases are pediatric, but it has also been reported in adults<ref>{{Cite journal|last=Ahmed|first=Maria Z.|last2=Venkatadasari|first2=Indrani|last3=Dyer|first3=Sara|last4=Wall|first4=Kerry|last5=Huxley|first5=Emma|last6=Lovell|first6=Richard|last7=Kishore|first7=Bhuvan|last8=Dassanayake|first8=Hansini|last9=Francis|first9=Sebastian|date=2022-11|title=Clonal evolution in adult TCF3::HLF-positive acute lymphoblastic leukemia undergoing stem cell transplantation|url=https://pubmed.ncbi.nlm.nih.gov/35907039|journal=Annals of Hematology|volume=101|issue=11|pages=2553–2554|doi=10.1007/s00277-022-04941-5|issn=1432-0584|pmid=35907039}}</ref><ref>{{Cite journal|last=Zeckanovic|first=Aida|last2=Mouttet|first2=Brice|last3=Vinti|first3=Luciana|last4=Ancliff|first4=Philip|last5=Brethon|first5=Benoît|last6=Cario|first6=Gunnar|last7=Elitzur|first7=Sarah|last8=Hazar|first8=Volkan|last9=Kunz|first9=Joachim|date=2025-06-01|title=Update on long-term outcomes of a cohort of patients with TCF3::HLF-positive acute lymphoblastic leukemia treated with blinatumomab and stem cell transplantation|url=https://pubmed.ncbi.nlm.nih.gov/39911115|journal=Haematologica|volume=110|issue=6|pages=1373–1378|doi=10.3324/haematol.2024.286111|issn=1592-8721|pmc=12130763|pmid=39911115}}</ref>

Two major types of ''TCF3''::''HLF'' gene fusion have been identified<ref>{{Cite journal|last=Hunger|first=S. P.|last2=Devaraj|first2=P. E.|last3=Foroni|first3=L.|last4=Secker-Walker|first4=L. M.|last5=Cleary|first5=M. L.|date=1994-05-15|title=Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL|url=https://pubmed.ncbi.nlm.nih.gov/8180393|journal=Blood|volume=83|issue=10|pages=2970–2977|issn=0006-4971|pmid=8180393}}</ref><ref>{{Cite journal|last=Panagopoulos|first=Ioannis|last2=Micci|first2=Francesca|last3=Thorsen|first3=Jim|last4=Haugom|first4=Lisbeth|last5=Tierens|first5=Anne|last6=Ulvmoen|first6=Aina|last7=Heim|first7=Sverre|date=2012-12|title=A novel TCF3-HLF fusion transcript in acute lymphoblastic leukemia with a t(17;19)(q22;p13)|url=https://pubmed.ncbi.nlm.nih.gov/23181981|journal=Cancer Genetics|volume=205|issue=12|pages=669–672|doi=10.1016/j.cancergen.2012.10.004|issn=2210-7762|pmid=23181981}}</ref><ref>{{Cite journal|last=Lejman|first=Monika|last2=Włodarczyk|first2=Monika|last3=Zawitkowska|first3=Joanna|last4=Kowalczyk|first4=Jerzy R.|date=2020-04-03|title=Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL|url=https://pubmed.ncbi.nlm.nih.gov/32245383|journal=BMC medical genomics|volume=13|issue=1|pages=58|doi=10.1186/s12920-020-0709-y|issn=1755-8794|pmc=7118981|pmid=32245383}}</ref>.

* Type 1: ''TCF3'' (NM_003200.3) exon 16 fused to ''HLF'' (NM_002126.4) exon 4

Extremely poor prognosis, high resistance to conventional therapy, and early relapse

Frequently accompanied by disseminated intravascular coagulation (DIC) and hypercalcemia<ref>{{Cite journal|last=Hunger|first=S. P.|date=1996-02-15|title=Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis|url=https://pubmed.ncbi.nlm.nih.gov/8608207|journal=Blood|volume=87|issue=4|pages=1211–1224|issn=0006-4971|pmid=8608207}}</ref><ref>{{Cite journal|last=Matsunaga|first=Takayuki|last2=Inaba|first2=Toshiya|last3=Matsui|first3=Hirotaka|last4=Okuya|first4=Mayuko|last5=Miyajima|first5=Atsushi|last6=Inukai|first6=Takeshi|last7=Funabiki|first7=Tetsunori|last8=Endo|first8=Mikiya|last9=Look|first9=A. Thomas|date=2004-04-15|title=Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein|url=https://pubmed.ncbi.nlm.nih.gov/15070701|journal=Blood|volume=103|issue=8|pages=3185–3191|doi=10.1182/blood-2003-09-3022|issn=0006-4971|pmid=15070701}}</ref><ref>{{Cite journal|last=Minson|first=Katherine A.|last2=Prasad|first2=Pinki|last3=Vear|first3=Susan|last4=Borinstein|first4=Scott|last5=Ho|first5=Richard|last6=Domm|first6=Jennifer|last7=Frangoul|first7=Haydar|date=2013|title=t(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature|url=https://pubmed.ncbi.nlm.nih.gov/23346431|journal=Case Reports in Hematology|volume=2013|pages=563291|doi=10.1155/2013/563291|issn=2090-6560|pmc=3549381|pmid=23346431}}</ref><ref>{{Cite journal|last=Inukai|first=T.|last2=Hirose|first2=K.|last3=Inaba|first3=T.|last4=Kurosawa|first4=H.|last5=Hama|first5=A.|last6=Inada|first6=H.|last7=Chin|first7=M.|last8=Nagatoshi|first8=Y.|last9=Ohtsuka|first9=Y.|date=2007-02|title=Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19|url=https://pubmed.ncbi.nlm.nih.gov/17183364|journal=Leukemia|volume=21|issue=2|pages=288–296|doi=10.1038/sj.leu.2404496|issn=0887-6924|pmid=17183364}}</ref>.

''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<ref>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</ref>.

!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

|Common recurrent finding in B-ALL; may be mutually exclusive from deletions of ''BTG1'' and ''VPREB1''

|9

|9p21.3

|''CDKN2A/B''

|NA

|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.  

!Molecular Pathogenesis

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

==Gene Mutations (SNV/INDEL)==

''RAS'' pathway gene alterations were common in ''TCF3''::''HLF''-positive B-ALL cases<ref name=":1" /><ref name=":0" />.  

!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''<br />

|Activating mutations

|-

|''KRAS''<br />

|Activating mutations

|Oncogene

|NA

|Treatment potential with MAPK/MEK inhibitors

|-

|''PTPN11''

|Oncogene

|Recurrent

|NA

|No

|Treatment potential with MAPK/MEK inhibitors

|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Functional studies have demonstrated that ''TCF3''::''HLF'' promotes anchorage-independent growth in mouse fibroblast cells<ref>{{Cite journal|last=Yoshihara|first=T.|last2=Inaba|first2=T.|last3=Shapiro|first3=L. H.|last4=Kato|first4=J. Y.|last5=Look|first5=A. T.|date=1995-06|title=E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF|url=https://pubmed.ncbi.nlm.nih.gov/7760820|journal=Molecular and Cellular Biology|volume=15|issue=6|pages=3247–3255|doi=10.1128/MCB.15.6.3247|issn=0270-7306|pmc=230557|pmid=7760820}}</ref><ref>{{Cite journal|last=Inukai|first=T.|last2=Inaba|first2=T.|last3=Yoshihara|first3=T.|last4=Look|first4=A. T.|date=1997-03|title=Cell transformation mediated by homodimeric E2A-HLF transcription factors|url=https://pubmed.ncbi.nlm.nih.gov/9032268|journal=Molecular and Cellular Biology|volume=17|issue=3|pages=1417–1424|doi=10.1128/MCB.17.3.1417|issn=0270-7306|pmc=231866|pmid=9032268}}</ref> and inhibits apoptosis, thereby enhancing cell survival<ref>{{Cite journal|last=Inaba|first=T.|last2=Inukai|first2=T.|last3=Yoshihara|first3=T.|last4=Seyschab|first4=H.|last5=Ashmun|first5=R. A.|last6=Canman|first6=C. E.|last7=Laken|first7=S. J.|last8=Kastan|first8=M. B.|last9=Look|first9=A. T.|date=1996-08-08|title=Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor|url=https://pubmed.ncbi.nlm.nih.gov/8700228|journal=Nature|volume=382|issue=6591|pages=541–544|doi=10.1038/382541a0|issn=0028-0836|pmid=8700228}}</ref><ref>{{Cite journal|last=Inukai|first=T.|last2=Inaba|first2=T.|last3=Ikushima|first3=S.|last4=Look|first4=A. T.|date=1998-10|title=The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF|url=https://pubmed.ncbi.nlm.nih.gov/9742120|journal=Molecular and Cellular Biology|volume=18|issue=10|pages=6035–6043|doi=10.1128/MCB.18.10.6035|issn=0270-7306|pmc=109189|pmid=9742120}}</ref>.

Gene expression profiling of ''TCF3''::''HLF''-positive B-ALL cases further revealed extensive transcriptional reprogramming toward an aberrant, immature hematopoietic state<ref name=":0" />.

|''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

|-

|''CDKN2A/B''; deletions

 

 

Not applicable.

<references />

==Notes==

<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] 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 

<nowiki>*</nowiki>''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 {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:B_lymphoblastic_leukaemia/lymphoma_with_TCF3::HLF_fusion</nowiki>.