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}} | |||
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | ||
==Primary Author(s)*== | ==Primary Author(s)*== | ||
Aiko Otsubo, Ph.D. FACMG | |||
Aiko Otsubo Ph.D FACMG | |||
==WHO Classification of Disease== | ==WHO Classification of Disease== | ||
| Line 29: | Line 24: | ||
|- | |- | ||
|Subtype(s) | |Subtype(s) | ||
|B lymphoblastic leukaemia/lymphoma with TCF3::HLF fusion | |B-lymphoblastic leukaemia/lymphoma with ''TCF3''::''HLF'' fusion | ||
|} | |} | ||
| Line 35: | Line 30: | ||
{| class="wikitable" | {| class="wikitable" | ||
|Acceptable | |Acceptable | ||
|N/A | |N/A | ||
|- | |- | ||
|Not Recommended | |Not Recommended | ||
|B-lymphoblastic leukaemia/lymphoma with E2A::HLF fusion | |B-lymphoblastic leukaemia/lymphoma with ''E2A''::''HLF'' fusion | ||
|} | |} | ||
==Gene Rearrangements== | ==Gene Rearrangements== | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
| Line 53: | Line 46: | ||
!Clinical Relevance Details/Other Notes | !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 | |''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 | |Rare (<1% of childhood B-ALL cases) | ||
|D, P | |D, P | ||
|Yes (WHO, NCCN) | |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 | |||
* 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<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== | ==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" | ||
|- | |- | ||
| Line 76: | Line 74: | ||
|9 | |9 | ||
|Loss | |Loss | ||
| | |9p13 | ||
| | |''PAX5'' | ||
| | |NA | ||
|No | |No | ||
|Common recurrent finding in | |Common recurrent finding in B-ALL; may be mutually exclusive from deletions of ''BTG1'' and ''VPREB1'' | ||
|- | |- | ||
|9 | |9 | ||
|Loss | |Loss | ||
| | |9p21.3 | ||
| | |''CDKN2A/B'' | ||
| | |NA | ||
|No | |No | ||
|Common recurrent finding in | |Common recurrent finding in various cancers | ||
|- | |- | ||
|12 | |12 | ||
| Line 94: | Line 92: | ||
|12q21.33 | |12q21.33 | ||
|''BTG1'' | |''BTG1'' | ||
| | |NA | ||
|No | |No | ||
|Common recurrent finding in B-ALL | |Common recurrent finding in B-ALL; may co-occur with deletion of ''VPREB1''; may be mutually exclusive from deletions of ''PAX5'' | ||
|- | |- | ||
|22 | |22 | ||
|Loss | |Loss | ||
|22q11.2 | |22q11.2 | ||
|VPREB1 | |''VPREB1'' | ||
| | |NA | ||
|No | |No | ||
|Common recurrent finding in B-ALL | |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== | ==Characteristic Chromosomal or Other Global Mutational Patterns== | ||
Not applicable. | Not applicable. | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
| Line 118: | Line 116: | ||
!Clinical Relevance Details/Other Notes | !Clinical Relevance Details/Other Notes | ||
|- | |- | ||
| | |NA | ||
|NA | |||
|NA | |||
|NA | |||
|NA | |||
|NA | |||
| | |||
| | |||
| | |||
| | |||
| | |||
|} | |} | ||
==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" />. | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
| Line 151: | Line 133: | ||
!Clinical Relevance Details/Other Notes | !Clinical Relevance Details/Other Notes | ||
|- | |- | ||
| | |''NRAS''<br /> | ||
|Activating mutations | |||
<br /> | |Oncogene | ||
| | |Common | ||
| | |NA | ||
| | |No | ||
| | |Treatment potential with MAPK/MEK inhibitors | ||
| | |||
| | |||
|- | |- | ||
| | |''KRAS''<br /> | ||
<br /> | |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 [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. | |}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. | ||
==Epigenomic Alterations== | ==Epigenomic Alterations== | ||
Not applicable. | Not applicable. | ||
==Genes and Main Pathways Involved== | ==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 | ''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>. | ||
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" />. | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | ||
|- | |- | ||
|''TCF3 and HLF'' | |''TCF3 and HLF;'' fusion creates chimeric protein | ||
|Lymphoid differentiation | |Lymphoid differentiation | ||
|Abnormal gene expression | |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== | ==Genetic Diagnostic Testing Methods== | ||
Karyotype | 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== | ==Familial Forms== | ||
| Line 217: | Line 198: | ||
==Additional Information== | ==Additional Information== | ||
Not applicable. | |||
==Links== | ==Links== | ||
[[TCF3]] | [[TCF3]] | ||
==References== | ==References== | ||
<references /> | <references /> | ||
==Notes== | ==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. | <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): | 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>. | |||
<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]] | ||