TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia.

Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co-immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

[1]  Tony Hunter,et al.  p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21 , 1994, Cell.

[2]  M. Ohki,et al.  t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Watkins,et al.  Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cells. , 1992, Cancer genetics and cytogenetics.

[4]  N. Speck,et al.  Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor , 1993, Molecular and cellular biology.

[5]  R. Gelber,et al.  Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  F. Mitelman,et al.  Catalog of Chromosome Aberrations in Cancer , 1996, British Journal of Cancer.

[7]  E. Macintyre,et al.  High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. , 1995, Blood.

[8]  C. Pui,et al.  Impact of three methods of treatment intensification on acute lymphoblastic leukemia in children: long-term results of St Jude total therapy study X. , 1992, Leukemia.

[9]  C. Bartram,et al.  Polymerase chain reaction analysis of BCR-ABL sequences in adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. , 1992, Leukemia.

[10]  Todd R. Golub,et al.  Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation , 1994, Cell.

[11]  P. Marynen,et al.  TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13). , 1995, Blood.

[12]  C. Klämbt,et al.  The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. , 1993, Development.

[13]  J. Rowley,et al.  Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Weissenbach,et al.  Loss of heterozygosity in the chromosomal region 12p12-13 is very common in childhood acute lymphoblastic leukemia and permits the precise localization of a tumor-suppressor gene distinct from p27KIP1. , 1995, Blood.

[15]  Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update). , 1991 .

[16]  S. Perrin,et al.  Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Young,et al.  Cancer incidence, survival, and mortality for children younger than age 15 years , 1986, Cancer.

[18]  L. Wiedemann,et al.  The novel activation of ABL by fusion to an ets-related gene, TEL. , 1995, Cancer research.

[19]  S. Bohlander,et al.  Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia. , 1996, Cancer research.

[20]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[21]  Bernard R. Rosner,et al.  Fundamentals of Biostatistics. , 1992 .

[22]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Raimondi.  Current Status of Cytogenetic Research in Childhood Acute Lymphoblastic Leukemia , 1993 .

[24]  Y. Yazaki,et al.  Generation of the AML1‐EVI‐1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. , 1994, The EMBO journal.

[25]  Michael L. Cleary,et al.  Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor , 1990, Cell.

[26]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[27]  A. Ganser,et al.  Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults , 1988 .

[28]  J. Rowley,et al.  The 3;21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  K. Ravichandran,et al.  The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. , 1994, The Journal of biological chemistry.

[30]  C. Reynolds,et al.  Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood. , 1995, Blood.

[31]  E. Thiel,et al.  Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by the polymerase chain reaction , 1991, The Lancet.

[32]  N. Lenny,et al.  The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation , 1995, Molecular and cellular biology.

[33]  P. Marynen,et al.  The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. , 1996, Blood.

[34]  James M. Roberts,et al.  TEL and KIP1 define the smallest region of deletions on 12p13 in hematopoietic malignancies. , 1995, Blood.

[35]  M. Schrappe,et al.  Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1. , 1996, Blood.

[36]  T. Golub,et al.  Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia , 1996, Molecular and cellular biology.

[37]  E. Soeda,et al.  Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. , 1995, Nucleic acids research.

[38]  F. Collins,et al.  Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. , 1993, Science.

[39]  S. Shurtleff,et al.  TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. , 1995, Leukemia.