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

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{{DISPLAYTITLE:B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion}}
{{DISPLAYTITLE:B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
 
{{Under Construction}}
 
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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). 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>


==Primary Author(s)*==
==Primary Author(s)*==


Put your text here<span style="color:#0070C0"> (''Name and affiliation; example:'' Jane Smith, PhD, Institute of Genomics) </span>
Aiko Otsubo, Ph.D. FACMG
 
==WHO Classification of Disease==
__TOC__
 
==Cancer Category / Type==
 
Put your text here
 
==Cancer Sub-Classification / Subtype==


Put your text here
==Definition / Description of Disease==
Put your text here <span style="color:#0070C0">(''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories referring to the specific WHO book pages, diagnostic criteria if applicable, and differential diagnosis if applicable'') </span>
==Synonyms / Terminology==
Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
==Epidemiology / Prevalence==
Put your text here
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
!Structure
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
!Disease
 
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|EXAMPLE Cytopenias
 
EXAMPLE Lymphocytosis (low level)
|}
 
==Sites of Involvement==
 
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; Example: nodal, extranodal, bone marrow'') </span>
 
==Morphologic Features==
 
Put your text here
 
==Immunophenotype==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|-
|Positive (universal)||EXAMPLE CD1
|Category
|B-cell lymphoid proliferations and lymphomas
|-
|-
|Positive (subset)||EXAMPLE CD2
|Family
|Precursor B-cell neoplasms
|-
|-
|Negative (universal)||EXAMPLE CD3
|Type
|B-lymphoblastic leukaemias/lymphomas
|-
|-
|Negative (subset)||EXAMPLE CD4
|Subtype(s)
|B-lymphoblastic leukaemia/lymphoma with ''TCF3''::''HLF'' fusion
|}
|}


==Chromosomal Rearrangements (Gene Fusions)==
==Related Terminology==


Put your text here and fill in the table
{| class="wikitable"
|Acceptable
|N/A
|-
|Not Recommended
|B-lymphoblastic leukaemia/lymphoma with ''E2A''::''HLF'' fusion
|}


==Gene Rearrangements==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Diagnostic Significance (Yes, No or Unknown)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|''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)
EXAMPLE 30% (add reference)
|Rare (<1% of childhood B-ALL cases)
|Yes
|D, P
|No
|Yes (WHO, NCCN)
|Yes
|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>
|EXAMPLE
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
* Type 2: ''TCF3'' exon 15 fused to ''HLF'' exon 4
 


The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
Extremely poor prognosis, high resistance to conventional therapy, and early relapse
|}
==Individual Region Genomic Gain / Loss / LOH==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>


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>.
==Individual Region Genomic Gain/Loss/LOH==
Of 13 reported cases<ref name=":1">{{Cite journal|last=Ma|first=Xiaotu|last2=Edmonson|first2=Michael|last3=Yergeau|first3=Donald|last4=Muzny|first4=Donna M.|last5=Hampton|first5=Oliver A.|last6=Rusch|first6=Michael|last7=Song|first7=Guangchun|last8=Easton|first8=John|last9=Harvey|first9=Richard C.|date=2015-03-19|title=Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/25790293|journal=Nature Communications|volume=6|pages=6604|doi=10.1038/ncomms7604|issn=2041-1723|pmc=4377644|pmid=25790293}}</ref><ref name=":0">{{Cite journal|last=Fischer|first=Ute|last2=Forster|first2=Michael|last3=Rinaldi|first3=Anna|last4=Risch|first4=Thomas|last5=Sungalee|first5=Stéphanie|last6=Warnatz|first6=Hans-Jörg|last7=Bornhauser|first7=Beat|last8=Gombert|first8=Michael|last9=Kratsch|first9=Christina|date=2015-09|title=Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options|url=https://pubmed.ncbi.nlm.nih.gov/26214592|journal=Nature Genetics|volume=47|issue=9|pages=1020–1029|doi=10.1038/ng.3362|issn=1546-1718|pmc=4603357|pmid=26214592}}</ref>, 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.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Prognostic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Therapeutic Significance (Yes, No or Unknown)
!Clinical Relevance Details/Other Notes
!Notes
|-
|-
|EXAMPLE
|9
 
|Loss
7
|9p13
|EXAMPLE Loss
|''PAX5''
|EXAMPLE
|NA
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
|Yes
|Yes
|No
|No
|EXAMPLE
|Common recurrent finding in B-ALL; may be mutually exclusive from deletions of ''BTG1'' and ''VPREB1''
 
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
|-
|-
|EXAMPLE
|9
 
|Loss
8
|9p21.3
|EXAMPLE Gain
|''CDKN2A/B''
|EXAMPLE
|NA
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|Common recurrent finding in various cancers
|-
|12
|Loss
|12q21.33
|''BTG1''
|NA
|No
|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
|No
|EXAMPLE
|Common recurrent finding in B-ALL; may co-occur with deletion of ''BTG1''; may be mutually exclusive from deletions of ''PAX5''
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
|}
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
 
Not applicable.
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: 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'')</span>
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE
|NA
 
|NA
Co-deletion of 1p and 18q
|NA
|Yes
|NA
|No
|NA
|No
|NA
|EXAMPLE:
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
|}
==Gene Mutations (SNV / INDEL)==
==Gene Mutations (SNV/INDEL)==
 
''RAS'' pathway gene alterations were common in ''TCF3''::''HLF''-positive B-ALL cases<ref name=":1" /><ref name=":0" />.  
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references 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.'') </span>
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|''NRAS''<br />
|Activating mutations
|Oncogene
|Common
|NA
|No
|Treatment potential with MAPK/MEK inhibitors
|-
|''KRAS''<br />
|Activating mutations
|Oncogene
|Recurrent
|NA
|No
|Treatment potential with MAPK/MEK inhibitors
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|''PTPN11''
 
|Gain of function
EXAMPLE:
|Oncogene
 
|Recurrent
EGFR; Exon 20 mutations
|NA
 
|No
EXAMPLE: BRAF; Activating mutations
|Treatment potential with MAPK/MEK inhibitors
|EXAMPLE: TSG
|}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.
|EXAMPLE: 20% (COSMIC)
 
EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
|
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
 
==Epigenomic Alterations==
==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<ref>{{Cite journal|last=Hunger|first=S. P.|last2=Ohyashiki|first2=K.|last3=Toyama|first3=K.|last4=Cleary|first4=M. L.|date=1992-09|title=Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/1516826|journal=Genes & Development|volume=6|issue=9|pages=1608–1620|doi=10.1101/gad.6.9.1608|issn=0890-9369|pmid=1516826}}</ref>.


Put your text here
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>.


==Genes and Main Pathways Involved==
Gene expression profiling of ''TCF3''::''HLF''-positive B-ALL cases further revealed extensive transcriptional reprogramming toward an aberrant, immature hematopoietic state<ref name=":0" />.
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|''TCF3 and HLF;'' fusion creates chimeric protein
|EXAMPLE: MAPK signaling
|Lymphoid differentiation
|EXAMPLE: Increased cell growth and proliferation
|Abnormal gene expression leads to stem-like state, anti-apoptotic signaling and differentiation arrest
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|''BCL2''; transcriptional upregulation
|EXAMPLE: Cell cycle regulation
|Anti-apoptosis
|EXAMPLE: Unregulated cell division
|Cell survival
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|''NRAS'', ''KRAS, PTPN11''; activating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|RAS/MAPK pathway
|EXAMPLE:  Abnormal gene expression program
|Cell proliferation
|-
|''CDKN2A/B''; deletions
|Cell cycle regulation
|Cell proliferation
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Karyotype analysis: fusion may be cryptic


Put your text here
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==
==Familial Forms==
 
Not applicable.
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>


==Additional Information==
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[[TCF3]]


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==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.
 
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'''EXAMPLE Book'''


#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.


==Notes==
<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>.
<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
<nowiki>*</nowiki>''Citation of this Page'': “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>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases B]]
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases B]]

Latest revision as of 20:14, 14 February 2026

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[1][2]

Two major types of TCF3::HLF gene fusion have been identified[3][4][5].

  • 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[6][7][8][9].

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

TCF3

References

  1. ↑ 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)
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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)
  5. ↑ 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)
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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)
  9. ↑ 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)
  10. ↑ 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. ↑ 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. ↑ 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)
  13. ↑ 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)
  14. ↑ 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)
  15. ↑ 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)
  16. ↑ 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.
  17. ↑ 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.

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