Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis.

Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 +/- 57 versus 1001 +/- 31 or versus 1315 +/- 76 fmol/nmol/h, P <.0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1-positive and TEL-AML1-negative ALL (P <.001, false discovery rate [FDR] = 5%). The pattern of expression of these 16 genes discriminated TEL-AML1-positive ALL with a true accuracy of 84% in an independent test set (n = 17, confidence interval 70% to 94%, P <.001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism.

[1]  A. Piga,et al.  Nucleoside incorporation into DNA and RNA in acute leukaemia: differences between the various leukaemia sub‐types , 1982, British journal of haematology.

[2]  J. Downing,et al.  Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells , 2003, Nature Genetics.

[3]  T. Golub,et al.  Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia. , 1998, Blood.

[4]  A. Gilles,et al.  Nucleoside diphosphate kinase from human erythrocytes. Structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme. , 1991, The Journal of biological chemistry.

[5]  S. Tomoyasu,et al.  Evaluation by multivariate analysis of the differentiation inhibitory factor nm23 as a prognostic factor in acute myelogenous leukemia and application to other hematologic malignancies. , 1998, Blood.

[6]  中山 利浩.  Expression in human hepatocellular carcinoma of nucleoside diphosphate kinase, a homologue of the nm23 gene product , 1993 .

[7]  O. Myklebost,et al.  Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression. , 1992, Cancer research.

[8]  H. Kovar,et al.  Variability of nm23-H1/NDPK-A expression in human lymphomas and its relation to tumour aggressiveness. , 1996, British Journal of Cancer.

[9]  P. Steeg,et al.  H 2 Gene , nm 23 Identification of a Second Human Updated , 2006 .

[10]  Y. Pekarsky,et al.  The murine Fhit locus: isolation, characterization, and expression in normal and tumor cells. , 1998, Cancer research.

[11]  S. P. Fodor,et al.  High density synthetic oligonucleotide arrays , 1999, Nature Genetics.

[12]  J. Downing,et al.  Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. , 2002, Cancer cell.

[13]  F. Sigaux,et al.  Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. , 1994, Blood.

[14]  C. Pui,et al.  Allopurinol inhibits de novo purine synthesis in lymphoblasts of children with acute lymphoblastic leukemia. , 1996, Leukemia.

[15]  J. Downing,et al.  AML1, the Target of Multiple Chromosomal Translocations in Human Leukemia, Is Essential for Normal Fetal Liver Hematopoiesis , 1996, Cell.

[16]  J. Harbott,et al.  Treatment response and residual-disease monitoring in initial and relapsed TEL-AML1 positive childhood ALL , 2001, Leukemia.

[17]  J. Downing,et al.  Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. , 2003, Blood.

[18]  J. Chang,et al.  Aberrant FHIT transcripts in acute myeloid leukaemia , 1997, British journal of haematology.

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

[20]  Maria Grazia Valsecchi,et al.  Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials , 1997 .

[21]  H P Koeffler,et al.  TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. , 1996, Blood.

[22]  K. Theil,et al.  TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia. , 2000, Cancer genetics and cytogenetics.

[23]  A. Lehninger.  Principles of Biochemistry , 1984 .

[24]  K. Umezawa,et al.  Induction by the guanosine analogue oxanosine of reversion toward the normal phenotype of K-ras-transformed rat kidney cells. , 1989, Cancer research.

[25]  M. Diccianni,et al.  Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy. , 1996, Blood.

[26]  D. Le Paslier,et al.  The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. , 1995, Blood.

[27]  P. Steeg,et al.  The potential roles of nm23 in cancer metastasis and cellular differentiation. , 1995, European journal of cancer.

[28]  S. Hino,et al.  Feedback Inhibition of Amidophosphoribosyltransferase Regulates the Rate of Cell Growth via Purine Nucleotide, DNA, and Protein Syntheses* , 2001, The Journal of Biological Chemistry.

[29]  A. Borkhardt,et al.  Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. , 1997, Blood.

[30]  R. Pieters,et al.  Hypoxanthine‐guanine phosphoribosyl‐transferase in childhood leukemia: Relation with immunophenotype, in vitro drug resistance and clinical prognosis , 1992, International journal of cancer.

[31]  R. Jackson,et al.  IMP dehydrogenase, an enzyme linked with proliferation and malignancy , 1975, Nature.

[32]  D. Campana,et al.  Childhood acute lymphoblastic leukaemia--current status and future perspectives. , 2001, The Lancet. Oncology.

[33]  C. Bruyn,et al.  Purine metabolism in relation to leukemia and lymphoid cell differentiation. , 1982 .

[34]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[35]  C. Croce,et al.  Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Downing,et al.  Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells , 2003, Nature Genetics.

[37]  Y Fujiwara,et al.  The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. , 1998, Genes & development.

[38]  G. Reaman,et al.  Purine pathway enzyme abnormalities in acute lymphoblastic leukemia. , 1981, Cancer research.

[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.

[40]  M. Greaves,et al.  Molecular genetics, natural history and the demise of childhood leukaemia. , 1999, European journal of cancer.

[41]  J. Downing,et al.  TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  M. Kanehisa,et al.  Development of a chemical structure comparison method for integrated analysis of chemical and genomic information in the metabolic pathways. , 2003, Journal of the American Chemical Society.

[43]  M. Greaves,et al.  TEL-AML1 fusion gene frequency in paediatric acute lymphoblastic leukaemia in Brazil. , 2000 .

[44]  L. Liotta,et al.  Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. , 1989, Cancer research.

[45]  H. Tashiro,et al.  Expression of metastasis-related nm23-H1 and nm23-H2 genes in ovarian carcinomas: correlation with clinicopathology, EGFR, c-erbB-2, and c-erbB-3 genes, and sex steroid receptor expression. , 1994, Cancer research.

[46]  M. Relling,et al.  De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo. , 2002, Blood.

[47]  F. Behm,et al.  Genetic studies of childhood acute lymphoblastic leukemia with emphasis on p16, MLL, and ETV6 gene abnormalities: results of St Jude Total Therapy Study XII , 1997, Leukemia.

[48]  F. Collart,et al.  Cell differentiation and altered IMP dehydrogenase expression induced in human T-lymphoblastoid leukemia cells by mycophenolic acid and tiazofurin. , 1990, Experimental cell research.

[49]  E. Scholar,et al.  Identification of the enzymatic pathways of nucleotide metabolism in human lymphocytes and leukemia cells. , 1973, Cancer research.

[50]  M. Relling,et al.  Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate. , 1996, The Journal of clinical investigation.

[51]  C. Pui,et al.  Acute lymphoblastic leukemia. , 1998, The New England journal of medicine.

[52]  J. Mason,et al.  Folate and carcinogenesis: an integrated scheme. , 2000, The Journal of nutrition.

[53]  L. Cannizzaro,et al.  FHIT gene transcript alterations occur frequently in myeloproliferative and myelodysplastic diseases , 1998, Cytogenetic and Genome Research.

[54]  A. Borkhardt,et al.  Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Study Group. , 1997, Blood.