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t(1;19)(q23;p13) TCF3/PBX1

Identity

Note Balanced form: -1, -19, +der(1), +der(19); unbalanced form: -19, +der(19).
 
  Balanced t(1;19)(q23;p13) (top left) and der(19) t(1;19)(q23;p13) G-banding (bottom left) - Courtesy Jean-Luc Lai; and R-banding (right) top: - Editor, below: - Courtesy Christiane Charrin.

Clinics and Pathology

Disease B Lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1); mostly found in ALL, L1/L2 type; exceptionally found in L3-like ALL, T-ALL, NHL, or AML.
Phenotype / cell stem origin Most cases: 'pre B' (cIg+) ALL; may be cIg- or sIg+.
CD45dim, CD19pos, CD34neg, CD22pos/dim, CD20dim/pos, CD24pos, TdTpos, CD10neg/dim, cIgMpos, CD9pos, CD15neg, CD65neg, CD66cneg, CD13neg, CD33neg.
Epidemiology 5% of ALL, or 20% of pre B ALL; found in children and young adults (1-60 yrs, median: 10 yrs --> one of the most frequent ALL in childhood (4-6%)); 3 male/4 female patients.
Clinics Moderate organomegaly; frequent CNS involvement; blood data: high WBC (median 20 x 109/L); high LDH.
Treatment Treatment should be adapted to biological features at the moment of diagnosis and also to early chemotherapy response and risk group stratification should not be based on TCF3-PBX1 detection.
Prognosis Although this chromosomal abnormality usually discloses adverse prognostic features (WBC, SNC), it is associated with good prognosis with modern intensive protocols. Median 5 yr-event free survival probability in childhood ALL: 85(6)%; no age or blood data prognostic significance; there are no differences between the prognosis of balanced or unbalanced forms. Prognosis in adults is not different between TCF3-PBX1 positive and negative cases (pEFS: 40 vs. 44%).

Cytogenetics

Cytogenetics Morphological Breakpoint is in 19p13.3; two different forms (see diagrams above): - the balanced t(1;19), one fourth of cases, with a der(1) and a der(19); - the unbalanced form, found in 3/4 cases, with 2 normal chromosomes 1, a der(19), and 1 normal chromosome 19: --> partial trisomy for 1q23-1qter and monosomy for 19p13.3-pter; the 2 forms can be in mosaic; note: 19p13 and 19q13 may be confused (e.g. literature reports). A subset of ALL usually hyperdyploid B-ALL has an identical t(1;19) that lack the expected phenotype probably do not represent TCF3-PBX1 B-ALL.
Additional anomalies t(17;19)(q22;p13) is not stricto sensu a variant, but, so far, an equivalent, with HLF (hepatic leukemia factor), on 17q22, involved in the translocation. Additional anomalies are found in half of the cases, mostly partial dup (1q), +6, del(6q), +8, i(9q), +17, i(17q), +21.

Genes involved and Proteins

Note The following are (most often) involved, except in some cases lacking the cIg expression:
Gene Name PBX1 (pre-B-cell leukemia homeobox 1)
Location 1q23.3
Note Previously known as "pre-B-cell leukemia transcription factor 1".
 
  c-PBX1 at 1q23 in normal cells: PAC 1146N1 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Dna / Rna Alternate splicing (variants 1, 2 and 3) (Acc Numbers: NM_001204963.1, NM_001204961.1 and NM_002585.3).
Protein Nuclear protein that belongs to the PBX homeobox family of transcriptional factors. Contains a homeodomain to bind to DNA.
Gene Name TCF3 (transcription factor 3)
Location 19p13.3
Note Other names: bHLHb21, E2A, "E2A immunoglobulin enhancer-binding factor E12/E47", E47, "immunoglobulin transcription factor 1", ITF1, "kappa-E2-binding factor", MGC129647, MGC129648, "transcription factor E2-alpha", VDIR, "VDR interacting repressor".
Dna / Rna Alternate splicing 2 isoforms --> E12 and E47. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9.
Protein Contains transcriptional activation domains and a basic helix-loop-helix DNA binding site; binds specifically to an immunoglobulin enhancer; nuclear localization; transcription factor.

Result of the chromosomal anomaly

Hybrid gene
Description 5' TCF3 exons fused to 3' PBX1; breakpoints are clustered on both genes; the reciprocal 5' PBX1 - 3' E2A is not transcribed.
Transcript Most cases present fusion of exons 1-16 in TCF3 to exons 4-9 in PBX1. Alternative breakpoint in intron 4 of PBX1, not detectable by standardized RT-PCR primers, has been reported.
  
Fusion Protein
 
Description 550 amino acids; 85 kDa; N-term transcriptional activation domains from TCF3 fused to the Hox cooperative motif and homeodomain of C-term PBX1; potent transcriptional activator.
Expression Localisation Nuclear localisation.
Oncogenesis Pleiotropic transforming activity. The resulting fusion protein (TCF3-PBX1), in which the DNA binding domain of E2A is replaced by the DNA binding domain of TCF3, transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members the PBX protein family.
  

Other genes implicated (Data extracted from papers in the Atlas)

Genes TCF3 PBX1

Translocations implicated (Data extracted from papers in the Atlas)

 t(1;19)(q23;p13) TCF3/PBX1

External links

Mitelman database Mitelman database (CGAP - NCBI)
t(1;19)(q23;p13) - Mitelman database (CGAP - NCBI)
COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMapTopo ( C42) Morph ( 9818/3) - arrayMap (Zurich)

Bibliography

A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL.
Kamps MP, Murre C, Sun XH, Baltimore D.
Cell. 1990 Feb 23;60(4):547-55.
PMID 1967983
 
Molecular analysis of the t(1;19) breakpoint cluster region in pre-B cell acute lymphoblastic leukemias.
Mellentin JD, Nourse J, Hunger SP, Smith SD, Cleary ML.
Genes Chromosomes Cancer. 1990 Sep;2(3):239-47.
PMID 2078515
 
Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor.
Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E, Smith SD, Cleary ML.
Cell. 1990 Feb 23;60(4):535-45.
PMID 1967982
 
PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.
Monica K, Galili N, Nourse J, Saltman D, Cleary ML.
Mol Cell Biol. 1991 Dec;11(12):6149-57.
PMID 1682799
 
Different molecular consequences of the 1;19 chromosomal translocation in childhood B-cell precursor acute lymphoblastic leukemia.
Privitera E, Kamps MP, Hayashi Y, Inaba T, Shapiro LH, Raimondi SC, Behm F, Hendershot L, Carroll AJ, Baltimore D, et al.
Blood. 1992 Apr 1;79(7):1781-8.
PMID 1348433
 
Prognostic significance of the balanced t(1;19) and unbalanced der(19)t(1;19) translocations in acute lymphoblastic leukemia.
Secker-Walker LM, Berger R, Fenaux P, Lai JL, Nelken B, Garson M, Michael PM, Hagemeijer A, Harrison CJ, Kaneko Y, et al.
Leukemia. 1992 May;6(5):363-9.
PMID 1593901
 
Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation.
Lu Q, Wright DD, Kamps MP.
Mol Cell Biol. 1994 Jun;14(6):3938-48.
PMID 7910944
 
Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative.
Pui CH, Raimondi SC, Hancock ML, Rivera GK, Ribeiro RC, Mahmoud HH, Sandlund JT, Crist WM, Behm FG.
J Clin Oncol. 1994 Dec;12(12):2601-6.
PMID 7989935
 
Heterogeneity of t(1;19)(q23;p13) acute leukaemias. French Haematological Cytology Group.
Troussard X, Rimokh R, Valensi F, Leboeuf D, Fenneteau O, Guitard AM, Manel AM, Schillinger F, Leglise C, Brizard A, et al.
Br J Haematol. 1995 Mar;89(3):516-26.
PMID 7734349
 
Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis.
Hunger SP.
Blood. 1996 Feb 15;87(4):1211-24.
PMID 8608207
 
Acute lymphoblastic leukemia.
Pui CH, Evans WE.
N Engl J Med. 1998 Aug 27;339(9):605-15. (REVIEW)
PMID 9718381
 
Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group.
Uckun FM, Sensel MG, Sather HN, Gaynon PS, Arthur DC, Lange BJ, Steinherz PG, Kraft P, Hutchinson R, Nachman JB, Reaman GH, Heerema NA.
J Clin Oncol. 1998 Feb;16(2):527-35.
PMID 9469337
 
Antigen expression patterns reflecting genotype of acute leukemias.
Hrusak O, Porwit-MacDonald A.
Leukemia. 2002 Jul;16(7):1233-58. (REVIEW)
PMID 12094248
 
The biology and therapy of adult acute lymphoblastic leukemia.
Faderl S, Jeha S, Kantarjian HM.
Cancer. 2003 Oct 1;98(7):1337-54. (REVIEW)
PMID 14508819
 
Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia.
Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M, Hunger SP.
Leukemia. 2005 May;19(5):806-13.
PMID 15744350
 
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.
Swerdlow SH, Campo E, Harris NL, Pileri SA, Stein H, Thiele J, Vardiman JW.
4th Edition. Lyon, France: IARC Press; 2008.
 
Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia.
Burmeister T, Gokbuget N, Schwartz S, Fischer L, Hubert D, Sindram A, Hoelzer D, Thiel E.
Haematologica. 2010 Feb;95(2):241-6. Epub 2009 Aug 27.
PMID 19713226
 
Prognostic impact of t(1;19)/ TCF3-PBX1 in childhood acute lymphoblastic leukemia in the context of Berlin-Frankfurt-Munster-based protocols.
Felice MS, Gallego MS, Alonso CN, Alfaro EM, Guitter MR, Bernasconi AR, Rubio PL, Zubizarreta PA, Rossi JG.
Leuk Lymphoma. 2011 Jul;52(7):1215-21. Epub 2011 May 3.
PMID 21534874
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

Contributor(s)

Written10-1997Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France
Updated07-2012Cristina N Alonso
Hematology-Oncology Department, Hospital Nacional de Pediatria Garrahan, Combate de los Pozos 1881- Zip Code : 1245. Buenos Aires, Republica Argentina

Citation

This paper should be referenced as such :
Alonso, CN
t(1;19)(q23;p13) TCF3/PBX1
Atlas Genet Cytogenet Oncol Haematol. 2013;17(1):45-47.
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. October 1997
URL : http://AtlasGeneticsOncology.org/Anomalies/t0119.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Jul 11 13:08:16 CEST 2014


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