Journal
LEUKEMIA
Volume 29, Issue 1, Pages 38-50Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2014.154
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Funding
- Medical Research Council, EuroCancerStemCell (6th framework EU integrated project)
- Hemato-Linne (Swedish Research Council)
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Fondo per gli Investimenti della Ricerca di Base (Programma 'Futuro in Ricerca' FIRB)
- Leukemia and Lymphoma Society fellowship
- Medical Research Council [G0801073, G0501838, MC_PC_12020] Funding Source: researchfish
- MRC [G0801073, MC_PC_12020] Funding Source: UKRI
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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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