Sorting leukemia initiating cells from adult and neonatal leukemia

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.