title: Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement.
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.
authors.affiliation: M Tettamanti Research Center, University of Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bardini
authors.affiliation: Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: P S
authors.initials: PS
authors.lastname: Woll
authors.affiliation: M Tettamanti Research Center, University of Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Corral
authors.affiliation: Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Luc
authors.affiliation: Hematopoietic Stem Cell Laboratory, Stem Cell Center, Lund, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Wittmann
authors.affiliation: Hematopoietic Stem Cell Laboratory, Stem Cell Center, Lund, Sweden.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Center of Pediatric Haematology Oncology, University of Catania, Catania, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lo Nigro
authors.affiliation: Laboratorio di Oncoematologia Pediatrica, Department of Pediatrics, University of Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: M Tettamanti Research Center, University of Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.affiliation: M Tettamanti Research Center, University of Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: S E W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D015321:Gene Rearrangement; D064593:Heterografts; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology*
chemical_list: C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase