Prenatal origin of acute lymphoblastic leukaemia in children

Wiemels, JL; Cazzaniga, Giovanni; Daniotti, Maria; Ob, Eden; Addison, G. M.; Masera, Giuseppe; Saha, Vaskar; Biondi, Andrea; Greaves, MF

doi:10.1016/s0140-6736(99)09403-9

Cited by 579 publications

(412 citation statements)

References 29 publications

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“…13,[25][26][27] This gene fusion has been detected in neonatal blood spots of patients who years later developed ALL, suggesting its origin in fetal development. 13,28,29 It is not clear, however, whether the occurrence and pathogenicity of this translocation is limited to a particular stage of early B-cell development. Although the TEL-AML1 fusion is considered to have a relatively good prognosis, 24,30,31 the biologic nature of leukemias carrying the t(12; 21) is heterogeneous.…”

Section: Discussionmentioning

confidence: 99%

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

Zaza

Yang

Kager

et al. 2004

Blood

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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. ( IntroductionPediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising different immunophenotypes and various genetic subtypes caused by chromosomal translocations with aberrant gene fusions and inappropriate expression of oncogenes. These genetic abnormalities have important prognostic and therapeutic implications, but the underlying mechanisms are not fully understood. 1 De novo purine synthesis (DNPS) is higher in ALL cells compared with normal bone marrow cells and peripheral blood lymphocytes, and T-lineage ALL has higher DNPS than B-lineage ALL. 2,3 It is not known, however, whether DNPS differs among the genetic subtypes of B-lineage ALL.Nucleotides play a key role in many biochemical processes related to their importance as DNA and RNA precursors, energy carriers, coenzyme components, and metabolic regulators. 4 Cells obtain purine nucleotides through 2 separate metabolic pathways, de novo purine synthesis and salvage of extracellular purine bases and nucleotides. DNPS and several enzymes involved in the purine metabolism pathway are important targets for antimetabolites (eg, mercaptopurine and methotrexate) that are the cornerstone of continuation therapy for childhood ALL. 1 DNPS is a complex pathway in which nucleotides are synthesized from amino acids and tetrahydrofolate in a multienzymatic process, starting with phosphoribosyl pyrophosphate (PRPP), primarily formed from ribose-5-phosphate (from the pentose phosphate pathway) and adenosine triphosphate (ATP). 4 Previous studies have shown that the pattern of gene expression in ALL blasts differs among ...

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Section: Discussionmentioning

confidence: 99%

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

Zaza

Yang

Kager

et al. 2004

Blood

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“…The striking age-incidence peak between 2 and 5 years of age consists mainly of common, B-cell precursor (BCP) ALL (Greaves et al, 1993(Greaves et al, , 1985McKinney et al, 1993;Buckley et al, 1994). Molecular data indicate that BCP ALL can arise in utero in association with acquired chromosomal rearrangements that result in covert preleukaemic clones (Wiemels et al, 1999;Greaves, 2006), but progression to clinical ALL requires additional clonal genetic abnormalities, accumulated in a variable postnatal latent period. These may arise under the influence of an immune response to delayed infection (McNally and Eden, 2004;Greaves, 2006), but lack of information incriminating a specific infectious agent (Greaves, 2006;MacKenzie et al, 2006) has hindered verification of this causal pathway.…”

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confidence: 99%

HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

et al. 2008

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Childhood B-cell precursor (BCP) ALL is thought to be caused by a delayed immune response to an unidentified postnatal infection. An association between BCP ALL and HLA class II (DR, DQ, DP) alleles could provide further clues to the identity of the infection, since HLA molecules exhibit allotype-restricted binding of infection-derived antigenic peptides. We clustered 430 HLA-DPB1 alleles into six predicted peptide-binding supertypes (DP1, 2, 3, 4, 6, and 8), based on amino acid di-morphisms at positions 11 (G/L), 69 (E/K), and 84 (G/D) of the DPb 1 domain. We found that the DPb11-69-84 supertype GEG (DP2), was 70% more frequent in BCP ALL (n ¼ 687; Po10 À4 ), and 98% more frequent in cases diagnosed between 3 and 6 years (Po10 À4 ), but not o3 or 46 years, than in controls. Only one of 21 possible DPB1 supergenotypes, GEG/GKG (DP2/DP4) was significantly more frequent in BCP ALL (P ¼ 0.00004) than controls. These results suggest that susceptibility to BCP ALL is associated with the DP2 supertype, which is predicted to bind peptides with positively charged, nonpolar aromatic residues at the P4 position, and hydrophobic residues at the P1 and P6 positions. Studies of peptide binding by DP2 alleles could help to identify infection(s) carrying these peptides.

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“…Recent studies have shed light on the natural history of this disease. Identification of leukaemia-associated translocations in neonatal blood spots (Guthrie cards) of children who will develop leukaemia years later indicates that the initiating event(s) of ALL usually occur before birth (Gale et al, 1997;Wiemels et al, 1999). Epidemiologic studies (Kinlen, 1988;Kinlen and Doll, 2004) suggest that at least one step in the process of ALL development involves an infectious agent (reviewed in Greaves, 2006).…”

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confidence: 99%

Adenovirus DNA is detected at increased frequency in Guthrie cards from children who develop acute lymphoblastic leukaemia

et al. 2007

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Prenatal origin of acute lymphoblastic leukaemia in children

Cited by 579 publications

References 29 publications

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

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

HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

Adenovirus DNA is detected at increased frequency in Guthrie cards from children who develop acute lymphoblastic leukaemia

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