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Acute Leukemias

Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement

Leukemia volume 21, pages 633–641 (2007)Cite this article

Abstract

The aim of this study was to identify immunobiological subgroups in 133 infant acute lymphoblastic leukemia (ALL) cases as assessed by their immunophenotype, immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement pattern, and the presence of mixed lineage leukemia (MLL) rearrangements. About 70% of cases showed the pro-B-ALL immunophenotype, whereas the remaining cases were common ALL and pre-B-ALL. MLL translocations were found in 79% of infants, involving MLL-AF4 (41%), MLL-ENL (18%), MLL-AF9 (11%) or another MLL partner gene (10%). Detailed analysis of Ig/TCR rearrangement patterns revealed IGH, IGK and IGL rearrangements in 91, 21 and 13% of infants, respectively. Cross-lineage TCRD, TCRG and TCRB rearrangements were found in 46, 17 and 10% of cases, respectively. As compared to childhood precursor-B-ALL, Ig/TCR rearrangements in infant ALL were less frequent and more oligoclonal. MLL-AF4 and MLL-ENL-positive infants demonstrated immature rearrangements, whereas in MLL-AF9-positive leukemias more mature rearrangements predominated. The immature Ig/TCR pattern in infant ALL correlated with young age at diagnosis, CD10 negativity and predominantly with the presence and the type of MLL translocation. The high frequency of immature and oligoclonal Ig/TCR rearrangements is probably caused by early (prenatal) oncogenic transformation in immature B-lineage progenitor cells with germline Ig/TCR genes combined with a short latency period.

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Acknowledgements

We are grateful to participants of the INTERFANT-99 study group for kindly providing infant ALL samples and to Paola de Lorenzo (Interfant-99 data center, Monza, Italy) for support in handling of the clinical data. We gratefully acknowledge DAKO (Glostrup, Denmark) for providing MLL probes for split-signal FISH. We are grateful to Danielle Jacobs and Ingrid Wolvers-Tetero for split-signal FISH analysis to AM Wijkhuijs for Southern blot analysis, to M de Bie and PG Hoogeveen for technical assistance, (Erasmus MC, Department of Immunology, Rotterdam, The Netherlands), to Jessica Buijs-Gladdines (Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands) and Elisabeth van Wering (Dutch Child Oncology Group, The Hague, Rotterdam) for sample collection and processing, to Wolf-Dieter Ludwig for immunophenotyping (Department of Hematology, Oncology and Tumor Immunology, Robert-Rössle-Clinic, HELIOS Clinic Berlin-Buch, Charité, Germany), to Oskar A. Haas for cytogenetics and FISH analysis (CCRI, Vienna, Austria), to T. Lion for RT–PCR analysis (CCRI, Vienna, Austria), and to Susi Fischer and Uli Monschein for technical assistance (CCRI, Vienna, Austria). We thank Marieke Comans-Bitter (Erasmus MC, Department of Immunology, Rotterdam, The Netherlands) for preparation of the figures. This study was performed on behalf of the INTERFANT-99 study group (coordinator: R. Pieters), which is composed of AIEOP (G. de Rossi, A. Biondi; Italy), ANZCHOG (R. Suppiah; Australia, New Zealand), Argentina (M. Felice), BFM-A (G. Mann; Austria), BFM-G (M. Schrappe; Germany), COALL (G Janka-Schaub; Germany), CWPGH (J. Stary; Czech Republic), DCOG (R. Pieters; the Netherlands), DFCI consortium (L Silverman; USA), EORTC-CLCG (A. Fester; France, Belgium, Portugal), FRALLE (F. Mechinaud; France), Hong Kong (CK Li), NOPHO (L Hovi; Scandinavian countries), PINDA (M Campbell; Chile), PPLLSG (T Szczepañski; Poland), SJCRH (JE Rubnitz; USA), UKCCSG (I Hann, A Vora; UK).

Financial support: Dutch Cancer Foundation (KWF grant EUR 2001–2441); Associazione Italiana Ricerca sul Cancro (AIRC): Regional Grant Cod.1105 to A.B; AIRC 2000 to G.B.; PIN 2004 to G.B.; Fonds zur Förderung der wissenschaftlichen Forschung (FWF P-13575-MED) to R.P-G; Deutsche Krebshilfe: 50-2698-Schr1; German BMBF Competence Network Pediatric Oncology/Hematology (Grant 01 Gi 9963/2).

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Authors and Affiliations

  1. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    M W J C Jansen, V H J van der Velden & J J M van Dongen

  2. Centro Ricerca Tettamanti, Pediatric Clinic, University of Milano Bicocca, Monza, Italy

    L Corral & A Biondi

  3. Children's Cancer Research Institute and, St Anna Kinderspital, Vienna, Austria

    R Panzer-Grümayer

  4. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    M Schrappe & A Schrauder

  5. Institute of Pharmaceutical Biology/ZAFES/DCAL, University of Frankfurt, Frankfurt/Main, Germany

    R Marschalek & C Meyer

  6. Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands

    M L den Boer & R Pieters

  7. Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands

    W J C Hop

  8. Interfant Trial Data,

    M G Valsecchi

  9. Department of Clinical Medicine and Prevention, Center, University of Milano-Bicocca, Italy

    M G Valsecchi

  10. Department of Pediatrics, University of Padova, Padova, Italy

    G Basso

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  1. M W J C Jansen
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Jansen, M., Corral, L., van der Velden, V. et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia 21, 633–641 (2007). https://doi.org/10.1038/sj.leu.2404578

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