Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia

The t(1;19) translocation yields a fusion between E2A and PBX1 genes and occurs in 5% of acute lymphoblastic leukemia in children and adults. We used chromosomal translocations and Ig heavy chain (IGH)/T cell antigen receptor (TCR) rearrangements to develop an understanding of the etiology and natural history of this subtype of leukemia. We sequenced the genomic fusion between E2A and PBX1 in 22 preB acute lymphoblastic leukemias and two cell lines. The prenatal origin of the leukemia was assessed in 15 pediatric patients by screening for the clonotypic E2A-PBX1 translocation in neonatal blood spots, or Guthrie cards, obtained from the children at the time of birth. Two patients were determined to be weakly positive for the fusion at the time of birth, in contrast to previously studied childhood leukemia fusions, t(12;21), t(8;21), and t(4;11), which were predominantly prenatal. The presence of extensive N-nucleotides at the point of fusion in the E2A-PBX1 translocation as well as specific characteristics of the IGH/TCR rearrangements provided additional evidence for a postnatal, preB cell origin. Intriguingly, 16 of 24 breakpoints on the 3.2-kb E2A intron 14 were located within 5 bp, providing evidence for a site-specific recombination mechanism. Breakpoints on the 232-kb PBX1 intron 1 were more dispersed but highly clustered proximal to exon 2. In sum, the translocation breakpoints displayed evidence of unique temporal, ontological, and mechanistic formation than the previously analyzed pediatric leukemia translocation breakpoints and emphasize the need to differentiate cytogenetic and molecular subgroups for studies of leukemia causality.

[1]  K. Rajewsky,et al.  Sequence homologies, N sequence insertion and JH gene utilization in VHDJH joining: implications for the joining mechanism and the ontogenetic timing of Ly1 B cell and B‐CLL progenitor generation. , 1990, The EMBO journal.

[2]  T. Szczepański,et al.  Cross-lineage T cell receptor gene rearrangements occur in more than ninety percent of childhood precursor-B acute lymphoblastic leukemias: alternative PCR targets for detection of minimal residual disease , 1999, Leukemia.

[3]  S. Raimondi,et al.  Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. , 1992, Science.

[4]  C. Geary.  Leukemia , 1984, British Journal of Cancer.

[5]  M. Greaves,et al.  Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. , 2001, Cancer research.

[6]  Genes, chromosomes & cancer , 1995 .

[7]  G. Rovera,et al.  Quantitation of leukemia clone-specific antigen gene rearrangements by a single-step PCR and fluorescence-based detection method , 1999, Leukemia.

[8]  K. Hagino-Yamagishi,et al.  [Oncogene]. , 2019, Gan to kagaku ryoho. Cancer & chemotherapy.

[9]  R. Hayes,et al.  Cancer Causes & Control , 2004, Cancer Causes & Control.

[10]  J. Potter,et al.  Maternal exposure to potential inhibitors of DNA topoisomerase II and infant leukemia (United States): A report from the Children's Cancer Group , 1996, Cancer Causes & Control.

[11]  E L Sonnhammer,et al.  Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, "minor" D segments or D-D recombination. , 1997, Journal of molecular biology.

[12]  M. Cleary,et al.  Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. , 1992, Genes & development.

[13]  M. Greaves,et al.  Microclustering of TEL‐AML1 translocation breakpoints in childhood acute lymphoblastic leukemia , 2000, Genes, chromosomes & cancer.

[14]  C. Murre,et al.  The role of E2A-PBX1 in leukemogenesis , 2001, Oncogene.

[15]  G. Rovera,et al.  Predominance of fetal type DJH joining in young children with B precursor lymphoblastic leukemia as evidence for an in utero transforming event , 1992, The Journal of experimental medicine.

[16]  H. Versmold,et al.  The diversity of rearranged immunoglobulin heavy chain variable region genes in peripheral blood B cells of preterm infants is restricted by short third complementarity-determining regions but not by limited gene segment usage. , 2001, Blood.

[17]  J. V. van Dongen,et al.  Extensive junctional diversity of gamma delta T-cell receptors expressed by T-cell acute lymphoblastic leukemias: implications for the detection of minimal residual disease. , 1991, Leukemia.

[18]  M. Lieber,et al.  Analysis of the V(D)J Recombination Efficiency at Lymphoid Chromosomal Translocation Breakpoints* , 2001, The Journal of Biological Chemistry.

[19]  A. Borkhardt,et al.  Presence of N regions in the clonotypic DJ rearrangements of the immunoglobulin heavy-chain genes indicates an exquisitely short latency in t(4;11)-positive infant acute lymphoblastic leukemia. , 2001, Blood.

[20]  S. Lewis,et al.  The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses. , 1994, Advances in immunology.

[21]  S. Lewis,et al.  Cryptic signals and the fidelity of V(D)J joining , 1997, Molecular and cellular biology.

[22]  H. Stein,et al.  Clinical relevance of immunoglobulin mutation analysis , 2000, Current opinion in oncology.

[23]  M. Segal,et al.  Clustering of Translocation Breakpoints , 2001 .

[24]  R. Marschalek,et al.  Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation , 1998, Oncogene.

[25]  F. E. Bertrand,et al.  IgM heavy chain complementarity-determining region 3 diversity is constrained by genetic and somatic mechanisms until two months after birth. , 1999, Journal of immunology.

[26]  J. Rowley,et al.  Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  B. Nadel,et al.  V(D)J-mediated Translocations in Lymphoid Neoplasms , 2002, The Journal of experimental medicine.

[28]  M. Greaves,et al.  Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. , 1999, Cancer research.

[29]  J. V. van Dongen,et al.  tal-1 deletions in T-cell acute lymphoblastic leukemia as PCR target for detection of minimal residual disease. , 1993, Leukemia.

[30]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[31]  M F Greaves,et al.  A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. , 1999, Cancer research.

[32]  B. Nadel,et al.  Novel Insights into the Mechanism of t(14;18)(q32;q21) Translocation in Follicular Lymphoma , 2001, Leukemia & lymphoma.

[33]  J. Fuscoe,et al.  V(D)J recombinase-like activity mediates hprt gene deletion in human fetal T-lymphocytes. , 1991, Cancer research.

[34]  A. Feeney,et al.  E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. , 2000, Molecular cell.

[35]  J. Shuster,et al.  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. , 1993, Blood.

[36]  E. Macintyre,et al.  Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease , 1999, Leukemia.

[37]  A. Feeney,et al.  Localized Gene-Specific Induction of Accessibility to V(D)j Recombination Induced by E2a and Early B Cell Factor in Nonlymphoid Cells , 2001, The Journal of experimental medicine.

[38]  T. Seriu,et al.  T cell receptor Dδ2Dδ3 rearrangement: a suitable allele-specific marker for the detection of minimal residual disease in childhood acute lymphoblastic leukemia , 1997, Leukemia.

[39]  J. Cayuela,et al.  The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype. , 2000, Blood.

[40]  B. Nadel,et al.  Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma. , 2001, Cancer research.

[41]  C. E. van der Schoot,et al.  B precursor acute lymphoblastic leukemia third complementarity‐determining regions predominantly represent an unbiased recombination repertoire: Leukemic transformation frequently occurs in fetal life , 1994, European journal of immunology.

[42]  Ana-Teresa Maia,et al.  In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. , 2002, Blood.

[43]  I. Sanz,et al.  Multiple mechanisms participate in the generation of diversity of human H chain CDR3 regions. , 1991, Journal of immunology.

[44]  G. M. Taylor,et al.  Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Segal,et al.  Molecular characterization of genomic AML1-ETO fusions in childhood leukemia , 2001, Leukemia.

[46]  M. Lieber,et al.  V(D)J recombination: a functional definition of the joining signals. , 1989, Genes & development.

[47]  M. Yamada,et al.  Preferential utilization of specific immunoglobulin heavy chain diversity and joining segments in adult human peripheral blood B lymphocytes , 1991, The Journal of experimental medicine.

[48]  B. Nadel,et al.  Alternative end-joining in follicular lymphomas’ t(14;18) translocation , 2002, Leukemia.

[49]  M. Greaves,et al.  Prenatal origin of acute lymphoblastic leukaemia in children , 1999, The Lancet.

[50]  Riccardo Dalla-Favera,et al.  Mechanisms of chromosomal translocations in B cell lymphomas , 2001, Oncogene.

[51]  M. Greaves,et al.  In utero rearrangements in the trithorax-related oncogene in infant leukaemias , 1993, Nature.

[52]  M. Greaves,et al.  Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[53]  O. Haas,et al.  Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL , 2001, Oncogene.

[54]  F. Behm,et al.  Cloning and sequence analysis of four t(9;11) therapy-related leukemia breakpoints , 1998, Leukemia.

[55]  F. Sigaux,et al.  Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias. , 1997, Blood.