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The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia.

R Grant RoweEdroaldo Lummertz da RochaPatricia SousaPavlos MissiosMichael MorseWilliam MarionAlena YermalovichJessica BarraganRonald MathieuDeepak Kumar JhaMark D FlemingTrista E NorthGeorge Q Daley
Published in: The Journal of experimental medicine (2019)
Leukemia phenotypes vary with age of onset. Delineating mechanisms of age specificity in leukemia could improve disease models and uncover new therapeutic approaches. Here, we used heterochronic transplantation of leukemia driven by MLL/KMT2A translocations to investigate the contribution of the age of the hematopoietic microenvironment to age-specific leukemia phenotypes. When driven by MLL-AF9, leukemia cells in the adult microenvironment sustained a myeloid phenotype, whereas the neonatal microenvironment supported genesis of mixed early B cell/myeloid leukemia. In MLL-ENL leukemia, the neonatal microenvironment potentiated B-lymphoid differentiation compared with the adult. Ccl5 elaborated from adult marrow stroma inhibited B-lymphoid differentiation of leukemia cells, illuminating a mechanism of age-specific lineage commitment. Our study illustrates the contribution of the developmental stage of the hematopoietic microenvironment in defining the age specificity of leukemia.
Keyphrases
  • acute myeloid leukemia
  • bone marrow
  • stem cells
  • induced apoptosis
  • dendritic cells
  • single cell
  • atrial fibrillation
  • oxidative stress
  • cell therapy
  • cell death
  • signaling pathway