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

Bardini, M; Woll, P S; Corral, L; Luc, S; Wittmann, Lilian LU ; Ma, Zhi LU ; Lo Nigro, L; Basso, G; Biondi, A and Cazzaniga, G, et al. (2015) In Leukemia 29(1). p.38-50
Abstract
Distinct from most other 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 a 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 immune-deficient mice, whereas other... (More)
Distinct from most other 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 a 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 immune-deficient 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.Leukemia accepted article preview online, 06 May 2014; doi:10.1038/leu.2014.154. (Less)
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Leukemia
volume
29
issue
1
pages
38 - 50
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Nature Publishing Group
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  • pmid:24798483
  • wos:000347673700005
  • scopus:84920704603
ISSN
1476-5551
DOI
10.1038/leu.2014.154
language
English
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yes
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b0b9fb70-1b7a-4e74-b4ef-622c33b2e895 (old id 4455783)
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http://www.ncbi.nlm.nih.gov/pubmed/24798483?dopt=Abstract
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2014-06-03 20:19:18
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2017-11-12 03:13:33
@article{b0b9fb70-1b7a-4e74-b4ef-622c33b2e895,
  abstract     = {Distinct from most other 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 a 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 immune-deficient 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.Leukemia accepted article preview online, 06 May 2014; doi:10.1038/leu.2014.154.},
  author       = {Bardini, M and Woll, P S and Corral, L and Luc, S and Wittmann, Lilian and Ma, Zhi and Lo Nigro, L and Basso, G and Biondi, A and Cazzaniga, G and Jacobsen, Sten Eirik W},
  issn         = {1476-5551},
  language     = {eng},
  number       = {1},
  pages        = {38--50},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement.},
  url          = {http://dx.doi.org/10.1038/leu.2014.154},
  volume       = {29},
  year         = {2015},
}