The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia

Authors

  • Mariana Emerenciano,

    1. Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
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  • Claus Meyer,

    1. Institute of Pharmaceutical Biology/ZAFES/Diagnostic Centre of Acute Leukaemia (DCAL), Goethe-University of Frankfurt, Frankfurt/Main, Germany
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  • Marcela B. Mansur,

    1. Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
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  • Rolf Marschalek,

    1. Institute of Pharmaceutical Biology/ZAFES/Diagnostic Centre of Acute Leukaemia (DCAL), Goethe-University of Frankfurt, Frankfurt/Main, Germany
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  • Maria S. Pombo-de-Oliveira,

    Corresponding author
    • Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
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  • The Brazilian Collaborative Study Group of Infant Acute Leukaemia

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    • The Brazilian Collaborative Study Group of Infant Acute Leukaemia members are listed in Appendix I as co-authors.

Correspondence: Maria S. Pombo-de-Oliveira, Paediatric Haematology-Oncology Program, Research Centre, Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, 37. Rio de Janeiro/RJ – Brasil. E-mail: mpombo@inca.gov.br

Summary

Acute leukaemia in early childhood - and mainly infant leukaemia (IL) – is characterized by acquired genetic alterations, most commonly by the presence of distinct MLL rearrangements (MLL-r). The aim of this study was to investigate possible correlations between clinical features and molecular analyses of a series of 545 childhood leukaemia (≤24 months of age) cases: 385 acute lymphoblastic leukaemia (ALL) and 160 acute myeloid leukaemia (AML). The location of the genomic breakpoints was determined in a subset of 30 MLL-r cases. The overall survival of the investigated cohort was 60·5%, as determined by the Kaplan-Meier method. Worse outcomes were associated with age at diagnosis ≤6 months (< 0·001), high white blood cell count (= 0·001), and MLL-r (= 0·002) in ALL, while children with AML displayed a poorer outcome (= 0·009) regardless of their age strata. Moreover, we present first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11. Based on the literature, most MLL-r IL display a breakpoint localization towards intron 11, which in turn may explain their worse clinical course. In summary, the MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor for MLL-r patients.

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