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Acute Leukemias

Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement

Leukemia volume 29, pages 38–50 (2015)Cite this article

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Abstract

Distinct from other forms of acute lymphoblastic leukemia (ALL), infant ALL with mixed lineage leukemia (MLL) gene rearrangement, the most common leukemia occurring within the first year of life, might arise without the need for cooperating genetic lesions. Through Ig/TCR rearrangement analysis of MLL-AF4+ infant ALL at diagnosis and xenograft leukemias from mice transplanted with the same diagnostic samples, we established that MLL-AF4+ infant ALL is composed of a branching subclonal architecture already at diagnosis, frequently driven by an Ig/TCR-rearranged founder clone. Some MLL-AF4+ clones appear to be largely quiescent at diagnosis but can reactivate and dominate when serially transplanted into immunodeficient mice, whereas other dominant clones at diagnosis can become more quiescent, suggesting a dynamic competition between actively proliferating and quiescent subclones. Investigation of paired diagnostic and relapse samples suggested that relapses often occur from subclones already present but more quiescent at diagnosis. Copy-number alterations identified at relapse might contribute to the activation and expansion of previously quiescent subclones. Finally, each of the identified subclones is able to contribute to the diverse phenotypic pool of MLL-AF4+ leukemia-propagating cells. Unraveling of the subclonal architecture and dynamics in MLL+ infant ALL may provide possible explanations for the therapy resistance and frequent relapses observed in this group of poor prognosis ALL.

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Acknowledgements

We thank A Castor for teaching the BM aspiration procedure, M Galbiati and A Lettieri for assistance in cytogenetic analysis and C Palmi and G Longinotti for counseling on IKZF1 deletion. We are grateful to Prof Mel Greaves for having inspired this study, Dr R Pieters responsible for the ‘Interfant Task Force’, Dr J van Dongen for fruitful discussion on clonal analysis in infant ALL, and all the many other clinicians involved. This work was supported by grants from the Medical Research Council, EuroCancerStemCell (6th framework EU integrated project) and Hemato-Linnè (Swedish Research Council) to SEJ; Associazione Italiana per la Ricerca sul Cancro (AIRC) to GC and AB; Fondo per gli Investimenti della Ricerca di Base (Programma ‘Futuro in Ricerca’ FIRB) to MB and AB, Leukemia and Lymphoma Society fellowship to PW. Fondazione Cariplo, Fondazione Tettamanti-Monza and Fondazione Città della Speranza-Padova.

Author contributions

SEJ and GC designed and supervised research and interpreted data; MB performed research and interpreted data, with help from PSW. MB and SEJ wrote the paper, with input from GC and PSW. LC contributed to the clonal analysis, LW provided assistance with mouse experiments, ZM performed FACS sorting and SL helped to interpret the FACS data. LLN cloned the MLL breakpoint, GB is responsible of the AIEOP cell bank and AB provided intellectual input on study design, results and interpretations. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. M Tettamanti Research Center, University of Milano Bicocca, Ospedale San Gerardo, Monza, Italy

    M Bardini, L Corral, A Biondi & G Cazzaniga

  2. Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, UK

    P S Woll, S Luc & S E W Jacobsen

  3. Hematopoietic Stem Cell Laboratory, Stem Cell Center, Lund, Sweden

    L Wittmann & Z Ma

  4. Center of Pediatric Haematology Oncology, University of Catania, Catania, Italy

    L Lo Nigro

  5. Department of Pediatrics, Laboratorio di Oncoematologia Pediatrica, University of Padova, Padova, Italy

    G Basso

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  1. M Bardini
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  4. S Luc
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Correspondence to G Cazzaniga or S E W Jacobsen.

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Bardini, M., Woll, P., Corral, L. et al. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. Leukemia 29, 38–50 (2015). https://doi.org/10.1038/leu.2014.154

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