View source for HAEM4:B-Lymphoblastic Leukemia/Lymphoma with TCF3 Rearrangements - Excluding t(1;19) and t(12;19)

{{DISPLAYTITLE:B-Lymphoblastic Leukemia/Lymphoma with TCF3 Rearrangements - Excluding t(1;19) and t(12;19)}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
{{Under Construction}}
==Primary Author(s)*==
Celeste Eno, PhD, Cedars-Sinai Medical Center 
==Cancer Category/Type==
B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) with ''TCF3'' variant fusions
==Cancer Sub-Classification / Subtype==
''TCF3::HLF'' Fusion t(17;19)(q22;p13.3)
==Definition / Description of Disease==
B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) with ''TCF3::HLF'' harbors a translocation between ''TCF3'' on chromosome 19 and ''HLF'' on chromosome 17. Variant ''TCF3'' fusions are not associated with the WHO-classified entity, t(1;19), due to a difference in prognosis although the clinical features and immunoprofiles are reportedly similar.
==Synonyms / Terminology==
''TCF3::HLF'' (''E2A::HLF'')
==Epidemiology / Prevalence==
t(17;19) is a rare translocation with an incidence of <1% in BCP-ALL and tends to present in pediatric and adolescents.<ref name=":5">{{Cite journal|last=Moorman|first=Anthony V.|date=2012-05|title=The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/22436535|journal=Blood Reviews|volume=26|issue=3|pages=123–135|doi=10.1016/j.blre.2012.01.001|issn=1532-1681|pmid=22436535}}</ref><ref name=":1" /><ref name=":6" /> 
==Clinical Features==
The presenting features are generally similar to those seen in patients with other ALL categories. Specific symptoms which have been noted to be associated with t(17;19) include coagulopathy and hypercalcemia.<ref name=":2" /> Patients with ''TCF3::HLF'' Type I fusions have been suggested to be associated with disseminated intravascular coagulation. Patients with ''TCF3::HLF'' Type II fusions have been associated with hypercalcemia. It has been hypothesized that hypercalcemia in t(17;19) patients is partly parathyroid hormone-related protein (PTHrP) mediated.<ref name=":2">{{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><ref name=":5" />
{| class="wikitable"
|'''Signs and  Symptoms'''
|B-symptoms  (weight loss, fever, night sweats)

Coagulopathy<ref name=":2" />

Type I: Disseminated intravascular coagulation<ref name=":2" /><ref name=":5" />

Type II: Hypercalcemia<ref name=":2" />
|-
|'''Laboratory  Findings'''
|
|}

==Sites of Involvement==
Bone Marrow and Peripheral Blood
==Morphologic Features==
There are no unique morphological or cytochemical features that distinguish this entity from other types of ALL.
==Immunophenotype==
t(17;19) display an immunoprofile similar to t(1;19). Cases of t(1;19)-ALL with concomitant ''TCF3::PBX1'' fusion invariably express a characteristic but uncommon profile of surface antigens. Blasts typically have a pre-B phenotype, with positivity for CD19, CD10, and cytoplasmic mu heavy chain. This diagnosis can be suspected even when cytoplasmic mu is not determined because these leukemias typically show strong expression of CD9 and lack CD34 or show very limited CD34 expression on only a minor subset of leukemic cells.<ref>{{Cite journal|last=Borowitz|first=M. J.|last2=Hunger|first2=S. P.|last3=Carroll|first3=A. J.|last4=Shuster|first4=J. J.|last5=Pullen|first5=D. J.|last6=Steuber|first6=C. P.|last7=Cleary|first7=M. L.|date=1993-08-15|title=Predictability of the t(1;19)(q23;p13) from surface antigen phenotype: implications for screening cases of childhood acute lymphoblastic leukemia for molecular analysis: a Pediatric Oncology Group study|url=https://pubmed.ncbi.nlm.nih.gov/8353275|journal=Blood|volume=82|issue=4|pages=1086–1091|issn=0006-4971|pmid=8353275}}</ref><ref>Borowitz, MJ, et al., (2017). B-lymphoblastic leukaemia/lymphoma 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.</ref>
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Cytoplasmic µ (cµ) heavy chain (pre-B phenotype); strong CD9; CD10; CD19
|-
|Positive (subset)||CD22
|-
|Negative (universal)||CD34; CD20 (Partial); CD21; Surface Immunoglobulin
|-
|Negative (subset)||
|}
==Chromosomal Rearrangements (Gene Fusions)==
[[File:TCF3 Rearrangements.png|thumb|''TCF3'' Rearrangements using "CyDAS Online Analysis Site", <nowiki>http://www.cydas.org/OnlineAnalysis/</nowiki><ref>{{Cite journal|last=Hiller|first=B.|last2=Bradtke|first2=J.|last3=Balz|first3=H.|last4=Rieder|first4=H.|date=2004-11-16|title=CyDAS: a cytogenetic data analysis system|url=http://dx.doi.org/10.1093/bioinformatics/bti146|journal=Bioinformatics|volume=21|issue=7|pages=1282–1283|doi=10.1093/bioinformatics/bti146|issn=1367-4803}}</ref>]]
''TCF3'' encodes several transcription factors via alternative splicing.  t (17;19) occurs in rare cases of ALL involving ''HLF'' (hepatic leukemia factor) on chromosome 17. The ''TCF3::HLF'' fusion gene encodes a chimeric transcription factor in which the transactivation domain of ''TCF3'' links to the basic leucine zipper dimerization and DNA-binding domain of ''HLF''.<ref>{{Cite journal|last=Inaba|first=T.|last2=Roberts|first2=W. M.|last3=Shapiro|first3=L. H.|last4=Jolly|first4=K. W.|last5=Raimondi|first5=S. C.|last6=Smith|first6=S. D.|last7=Look|first7=A. T.|date=1992-07-24|title=Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia|url=https://pubmed.ncbi.nlm.nih.gov/1386162|journal=Science (New York, N.Y.)|volume=257|issue=5069|pages=531–534|doi=10.1126/science.1386162|issn=0036-8075|pmid=1386162}}</ref><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>  There are two types of fusion: type 1 is generated by the fusion between exon 16 of ''TCF3'' and exon 4 of ''HLF'' with an insertion of cryptic exon (joining region) maintaining an open-reading frame, whereas type 2 is generated by the fusion between exon 15 of ''TCF3'' and exon 4 of ''HLF'' in the same reading frame.<ref name=":1">{{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>
{| class="wikitable"
|'''Chromosomal Rearrangement'''
|'''Genes in Fusion'''

'''(5’ or 3’ Segments)'''
|'''Pathogenic Derivative'''
|'''Prevalence'''
|'''Diagnostic  Significance (Yes, No or Unknown)'''
|'''Prognostic  Significance (Yes, No or Unknown)'''
|'''Therapeutic  Significance (Yes, No or Unknown)'''
|'''Notes'''
|-
|t(17;19)(q22;p13)
|5' ''TCF3'' / 3' ''HLF''
|der(19)
|<1%
|Yes
|Yes
|No
|There are two types of fusion: type 1 is generated by the fusion between exon 16 of ''TCF3'' and exon 4 of ''HLF'' with an insertion of cryptic exon (joining region) maintaining an open-reading frame, whereas type 2 is generated by the fusion between exon 15 of ''TCF3'' and exon 4 of ''HLF'' in the same reading frame.<ref name=":1" />
|}
<br />
==Characteristic Chromosomal Aberrations / Patterns==
Only a few cases have been reported; therefore, no characteristic patterns are noted as of yet. However, ~50% of cases may contain additional abnormalities<ref>{{Cite journal|last=Viguié|first=F|date=2011-02|title=t(17;19)(q22;p13)|url=http://dx.doi.org/10.4267/2042/37516|journal=Atlas of Genetics and Cytogenetics in Oncology and Haematology|issue=2|doi=10.4267/2042/37516|issn=1768-3262}}</ref> 

==Genomic Gain/Loss/LOH==
Only a few cases have been reported; therefore, no characteristic patterns are noted as of yet. One case demonstrated loss of 13q12.2q21.1 (containing ''RB1'') and intergenic duplication of ''NOTCH1.''<ref name=":3">{{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> It has described that up to 70% of ''TCF3::HLF'' cases have a concurrent ''PAX5'' deletion<ref name=":6">{{Cite journal|last=Akkari|first=Yassmine M.N.|last2=Bruyere|first2=Helene|last3=Hagelstrom|first3=R. Tanner|last4=Kanagal-Shamanna|first4=Rashmi|last5=Liu|first5=Jie|last6=Luo|first6=Minjie|last7=Mikhail|first7=Fady M.|last8=Pitel|first8=Beth A.|last9=Raca|first9=Gordana|date=2020-05|title=Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia|url=http://dx.doi.org/10.1016/j.cancergen.2020.03.001|journal=Cancer Genetics|volume=243|pages=52–72|doi=10.1016/j.cancergen.2020.03.001|issn=2210-7762}}</ref><ref name=":1" /> 
==Gene Mutations (SNV/INDEL)==
Very few studies have reported findings, and such studies focus on the specific fusion type. A study comparing t(1;19) (n=29) to t(17;19) (n= 12) cases reported recurrent intragenic deletions of ''PAX5'' or ''VPREB1'' in 2 cases of t(17;19) and RAS signaling pathway genes in 2 cases.<ref name=":1" /> Additionally a study of four t(17;19)‐ALL cell lines detected RAS pathway mutations in all four t(17;19)‐ALL lines.<ref name=":4">{{Cite journal|last=Watanabe|first=Atsushi|last2=Inukai|first2=Takeshi|last3=Kagami|first3=Keiko|last4=Abe|first4=Masako|last5=Takagi|first5=Masatoshi|last6=Fukushima|first6=Takashi|last7=Fukushima|first7=Hiroko|last8=Nanmoku|first8=Toru|last9=Terui|first9=Kiminori|date=2019-07-15|title=Resistance of t(17;19)‐acute lymphoblastic leukemia cell lines to multiagents in induction therapy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718581/|journal=Cancer Medicine|volume=8|issue=11|pages=5274–5288|doi=10.1002/cam4.2356|issn=2045-7634|pmc=6718581|pmid=31305009}}</ref>
{| class="wikitable"
|'''Gene;  Genetic Alteration'''
|'''Presumed  Mechanism (Tumor Suppressor Gene (TSG)/Oncogene/Other)'''
|'''Prevalence  (COSMIC/ TCGA/Other)'''
|'''Concomitant  Mutations'''
|'''Mutually  Exclusive Mutations'''
|'''Diagnostic Significance (Yes, No or  Unknown)'''
|'''Prognostic Significance'''

'''(Yes, No or Unknown)'''
|'''Therapeutic Significance'''

'''(Yes, No or Unknown)'''
|'''Notes'''
|-
|RAS family (''NRAS, KRAS, PTPN11, SPHK1''); Activating mutations<ref name=":1" />
|
|
|
|
|
|
|
|

|-
|''TCF3''
|
|
|
|
|
|
|
|One study found ''TCF3'' mutations on the non-fused, normal allele in relapsed/progressing cases.<ref name=":1" />
|}

==Epigenomics (Methylation)==
A single study comparing t(17;19) with t(1;19) found 7000 differentially methylated CpG sites between subtypes, of which 78% had lower methylation levels in ''TCF3::HLF''. ''KBTBD11'' differed in methylation and expression between subtypes and before and after remission in ''TCF3::HLF'' samples.<ref>{{Cite journal|last=Kachroo|first=Priyadarshini|last2=Szymczak|first2=Silke|last3=Heinsen|first3=Femke-Anouska|last4=Forster|first4=Michael|last5=Bethune|first5=Jörn|last6=Hemmrich-Stanisak|first6=Georg|last7=Baker|first7=Lewis|last8=Schrappe|first8=Martin|last9=Stanulla|first9=Martin|date=2018-02|title=NGS-based methylation profiling differentiates TCF3-HLF and TCF3-PBX1 positive B-cell acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/29334255|journal=Epigenomics|volume=10|issue=2|pages=133–147|doi=10.2217/epi-2017-0080|issn=1750-192X|pmid=29334255}}</ref>
==Genes and Main Pathways Involved==
The chimeric protein from ''TCF3::HLF'' acts as a transcription factor resulting in dedifferentiation of mature B lymphocytes.<ref name=":3" /> All ''TCF3'' fusions had expression profile signature of B lymphoid cells (''PAX5, BLK,'' ''CD19, CD22, CD79B, TCF3, EBF1, VPREB1, RAG1, ROR1, BLNK, DNTT)''. The differences between the ''TCF3'' fusion partners, ''PBX1'', ''HLF'', and ''ZNF384'', led to differential expression patterns based on the genes regulated by these partners. t(17;19) demonstrated induced expression of HLF- regulated genes (''SNAI2 (SLUG), GPC4'' and ''BMP3'').<ref name=":1" />
{| class="wikitable"
|'''Gene;  Genetic Alteration'''
|'''Pathway'''
|'''Pathophysiologic  Outcome'''
|-
|''TCF3::HLF''
|
|Dedifferentiation of mature B lymphocytes<ref name=":3" />
|}

==Diagnostic Testing Methods==

*Chromosome analysis
*Fluorescence in situ hybridization (FISH). Break-apart probes may be required to identify cases with cryptic translocations.
*Reverse transcriptase PCR (RT-PCR) may aid in diagnosis.<ref name=":0">{{Cite journal|last=Hirabayashi|first=Shinsuke|last2=Ohki|first2=Kentaro|last3=Nakabayashi|first3=Kazuhiko|last4=Ichikawa|first4=Hitoshi|last5=Momozawa|first5=Yukihide|last6=Okamura|first6=Kohji|last7=Yaguchi|first7=Akinori|last8=Terada|first8=Kazuki|last9=Saito|first9=Yuya|date=2017-01|title=ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype|url=https://pubmed.ncbi.nlm.nih.gov/27634205|journal=Haematologica|volume=102|issue=1|pages=118–129|doi=10.3324/haematol.2016.151035|issn=1592-8721|pmc=5210242|pmid=27634205}}</ref>
*Next generation sequencing (NGS)
*Mate pair sequencing (MPseq) to identify the fusion partners in G-band negative, ''TCF3'' BA + cases.<ref>{{Cite journal|last=Rowsey|first=Ross A.|last2=Smoley|first2=Stephanie A.|last3=Williamson|first3=Cynthia M.|last4=Vasmatzis|first4=George|last5=Smadbeck|first5=James B.|last6=Ning|first6=Yi|last7=Greipp|first7=Patricia T.|last8=Hoppman|first8=Nicole L.|last9=Baughn|first9=Linda B.|date=2019-10-01|title=Characterization of TCF3 rearrangements in pediatric B-lymphoblastic leukemia/lymphoma by mate-pair sequencing (MPseq) identifies complex genomic rearrangements and a novel TCF3/TEF gene fusion|url=https://pubmed.ncbi.nlm.nih.gov/31575852|journal=Blood Cancer Journal|volume=9|issue=10|pages=81|doi=10.1038/s41408-019-0239-z|issn=2044-5385|pmc=6773761|pmid=31575852}}</ref>

Determination of the fusion partner is necessary as there are significant prognostic differences between the recurrent ''TCF3::PBX1'' fusion and the less common fusions of ''TCF3::HLF'' or ''TCF3::ZNF384.''
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
The ''TCF3::HLF'' translocation, t (17;19), is associated with a dismal prognosis. A study found t(17;19) may be sensitive to certain drugs in animal models.<ref name=":1" /> An ''in vitro'' study using four t(17;19)‐ALL and sixteen t(1;19)‐ALL cell lines demonstrated the t(17;19)‐ALL cell lines were more resistant to vincristine (VCR), daunorubicin (DNR), and prednisolone (Pred) than t(1;19)‐ALL cell lines. In addition the t(17;19)‐ALL cell lines were less sensitive to three (Pred, VCR, and l‐asparaginase [l‐Asp]), four (Pred, VCR, l‐Asp, and DNR) and five (Pred, VCR, l‐Asp, DNR, and cyclophosphamide) agents, which are widely used in induction therapy.<ref name=":4" /> 

An ''in vitro'' study demonstrated cells harboring ''TCF3::HLF'' are sensitive to PARP inhibitors (olaparib and veliparib)<ref>{{Cite journal|last=Piao|first=Jinhua|last2=Takai|first2=Shiori|last3=Kamiya|first3=Takahiro|last4=Inukai|first4=Takeshi|last5=Sugita|first5=Kanji|last6=Ohyashiki|first6=Kazuma|last7=Delia|first7=Domenico|last8=Masutani|first8=Mitsuko|last9=Mizutani|first9=Shuki|date=2017-02-01|title=Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells|url=https://pubmed.ncbi.nlm.nih.gov/27894958|journal=Cancer Letters|volume=386|pages=131–140|doi=10.1016/j.canlet.2016.11.021|issn=1872-7980|pmid=27894958}}</ref>, as well as the ''BCL2'' specific inhibitor, venetoclax.<ref name=":1" />
==Familial Forms==
None reported
==Other Information==
Put your text here
==Links==
[[TCF3]]

''[[HLF]]''
==References==
(use "Cite" icon at top of page)<references />

==Notes==
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[[Category:HAEM4]] [[Category:DISEASE]]