GSE105086
The age of the hematopoietic microenvironment specifies lineage in MLL-rearranged leukemia [Ccl5]
The defining characteristics of leukemia, such as lineage and genetics, are associated with a typical age of onset.  Understanding mechanisms of leukemia age specificity could improve disease models to develop new therapies.  We used heterochronic transplantation of murine leukemia driven by MLL-AF9 to investigate the relative contribution of the age of the cell-of-origin or the hematopoietic microenvironment to the lineage fate of leukemia initiating cells (LICs).  We show that the neonatal hematopoietic niche supports the development of infant-like mixed lineage B-cell/myeloid leukemia, while a mature niche promotes adult-like pure acute myeloid leukemia (AML) from identical cells of origin.  We attribute this to inhibition of B-lymphoid fate in multipotent progenitor-like LICs by Ccl5 from adult bone marrow (BM) stroma, and implicate glycogen synthase kinase-3 (GSK-3) signaling in the myeloid fate specification in mouse and human MLL-driven leukemia.  These findings connect maturation and aging of the hematopoietic system to leukemia age specificity. Overall design: Primary neonatal murine leukemia treated with ccl5 or under control conditions