Prenatal origin of childhood acute lymphoblastic leukemia, association with birth weight and hyperdiploidy

Gruhn, Bernd; Jw, Taub; Ge, Yubin; Beck, JF; Zell, Roland; Häfer, Ralf; Fh, Hermann; Debatin, Klaus‐Michael; Steinbach, Daniel

doi:10.1038/leu.2008.152

Cited by 70 publications

(81 citation statements)

References 37 publications

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“…We thus propose a model for the timing of somatic recombination of IGH genes and the nondisjunction of chromosomes 14, which suggests that cells usually already have a DJ H rearrangement before the nondisjunction event, which presumably occurs already in utero. [25][26][27][28] Even though the immunogenetic data from this study strongly suggest that HeH forms are arrested in a more immature stage of differentiation than other genetic subgroups, 16 this fact is not at all reflected on the immunophenotypic level, since pre-B and common ALL immunophenotypes are equally frequent in the three major investigated BCP ALL categories (data not shown).…”

Section: Discussionmentioning

confidence: 85%

Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

et al. 2009

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Childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) is generally a clonal disease in which the number of IGH rearrangements per cell does not exceed the number of the IGH alleles on chromosome 14. Consequently, monoclonal high hyperdiploid (HeH) cases with a trisomy 14 can harbor three rearrangements, a pattern that otherwise may be misinterpreted to be oligoclonal. Oligoclonal IGH rearrangements, on the other hand, may be instable at relapse and should therefore not be used for minimal residual disease analysis. We thus investigated the association between IGH allele copy numbers and the IGH rearrangement patterns in 90 HeH BCP ALL with either two (13%) or three copies (87%) of chromosome 14. HeH cases (44%) had an oligoclonal IGH rearrangement pattern, but true oligoclonalityFafter correction for the respective copy number of IGH allelesFwas only 16%. Monoclonal and oligoclonal HeH cases had predominantly V H to preexisting DJ H recombinations, a finding that contrasts with oligoclonal cases of other major genetic BCP ALL subgroups in which V H replacements prevail. We conclude that for the precise assessment and correct interpretation of clonality patterns in BCP ALL, the IGH allele copy number has to be taken into consideration.

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Section: Discussionmentioning

confidence: 85%

Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

et al. 2009

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“…showed hyperdiploid leukemia clones (>50 chromosomes, Supplemental Results), a childhood B-ALL subtype that is very likely to be prenatally initiated (Gruhn et al 2008). However, chromosomal instabilities found in preleukemic clones are generated prenatally in the normal population at ;100 times the rate of overt ALL (Mori et al 2002), thus a second hit is required to trigger ALL during childhood and results from other genetic and/or environmental factors.…”

Section: Resultsmentioning

confidence: 99%

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

et al. 2012

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One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.

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“…[2][3][4][5][6][7][8][9][10][11] Unless the postnatal genetic hit(s) is inevitable, the prevalence of newborns harboring preleukemic first hit-cells should exceed the cumulative incidence of the corresponding leukemia. Accordingly, gene transcripts from the most common childhood ALL chromosomal translocation, t(12;21)(p13;q22)[ETV6-RUNX1], were demonstrated in approximately 1% of healthy newborns in one British study, 12 corresponding to 100-fold the cumulative incidence of ETV6-RUNX1-positive ALL in childhood.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of t(12;21)[ETV6-RUNX1]–positive cells in healthy neonates

Lausten-Thomsen¹,

Madsen

Vestergaard³

et al. 2011

Blood

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t(12;21)(p13;q22)[ETV6-RUNX1] is the most common chromosomal translocation in childhood acute lymphoblastic leukemia, and it can often be backtracked to Guthrie cards supporting prenatal initiation and high levels of circulating t(12;21)-positive cells at birth. To explore the prevalence of ETV6-RUNX1-positive cells in healthy neonates, mononuclear cells from 1417 umbilical cord blood samples were isolated within 24 hours from birth and subsequently screened for ETV6-RUNX1 transcripts using a highly sensitive real-time reverse transcription polymerase chain reaction assay. In first-run polymerase chain reaction, 14 samples were positive at levels below 10 ؊5 , of which specific hybridization reflecting the relevant genetic region was positive in 9 cases. Repeated analyses using stored mRNA and flowcytometric sorting of a CD19 ؉ , CD8 ؉ , and CD19 ؊ /CD8 ؊ subpopulations from cryopreserved mononuclear cells from the same cord blood samples (mean sorted: 18 ؋ 10 6 cells) revealed no positive findings, which demonstrates that the level and/or frequency of ETV6-RUNX1-positive cells is markedly lower than suggested in previous studies. IntroductionThe development of childhood B-cell lineage acute lymphoblastic leukemia (ALL) involves (at least) 2 genetic events (hits), 1 the first of which frequently arises prenatally. [2][3][4][5][6][7][8][9][10][11] Unless the postnatal genetic hit(s) is inevitable, the prevalence of newborns harboring preleukemic first hit-cells should exceed the cumulative incidence of the corresponding leukemia. Accordingly, gene transcripts from the most common childhood ALL chromosomal translocation, t(12;21)(p13;q22)[ETV6-RUNX1], were demonstrated in approximately 1% of healthy newborns in one British study, 12 corresponding to 100-fold the cumulative incidence of ETV6-RUNX1-positive ALL in childhood. 13 Noteworthy, the positive cells were reported to occur at levels of 10 Ϫ3 -10 Ϫ4 , and a threshold of 10 Ϫ5 was used for classification of t(12;2)-positive samples with no report of subthreshold frequencies. 12 Since these results are important for mapping the natural history of t(12;21)-positive ALL and furthermore limits the options for future screening, we assessed the prevalence of ETV6-RUNX-positive cells in 1417 newborns. MethodsMononucleated cells (MNCs) were isolated from umbilical cord blood (UCB) samples from healthy, full-term newborns through Ficoll density centrifugation 14 within 24 hours after birth to minimize cellular and/or mRNA degradation. 15 This study was approved by the Danish Data Protection Agency and the Danish Scientific Ethics Committee.mRNA from Ն 2.5 ϫ 10 6 MNCs was extracted using a KingFisher mL robot (ThermoFisher) and the MagAttrackDirect mRNA-M48 Kit (QIAGEN): 750 L of lysis solution, 75 L of magnetic beads, and 550 L of washing solution IϩII. mRNA was eluted in 50 L of RNase-free water, divided into 2 tubes, and stored at Ϫ80°C until use. Surplus MNCs were cryopreserved in liquid nitrogen. For subsequent flow cytometrically sorted subpopulations, mRNA was c...

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Prenatal origin of childhood acute lymphoblastic leukemia, association with birth weight and hyperdiploidy

Cited by 70 publications

References 37 publications

Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

Prevalence of t(12;21)[ETV6-RUNX1]–positive cells in healthy neonates

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