Critical Features Of Altered Hematopoietic Microenvironment And Mechanistic Findings In Mouse Leukemia Model

The leukemic progression originating from a minor population of AML cells inevitably surpasses normal hematopoiesis in vivo.Many previous observations have demonstrated that the leukemic progression probably involves the remodeling of the hematopoietic microenvironment,which favors the leukemic expansion at the expense of normal hematopoiesis.Nevertheless,the accurate underlying mechanisms remain largely unknown.Here we used a syngeneic transplantation model of acute myeloid leukemia(AML)cells,which were derived from PML/RAR? transgenic mice,to investigate the alterations of hematopoietic microenvironment during the development towards an overt AML phenotype in the recipients.We found that the decrease in normal hematopoietic activity was ascribed to a differentiation block of hematopoietic stem cells(HSCs)rather than an early depletion of HSCs.Notably,an obvious blockade in the generation of osteoblasts(OBs)from mesenchymal stem cells(MSCs),which was critically required to support the generation and expansion of myeloid and B lymphoid progenitors from HSCs,paralleled this pathological event.We confirmed that leukemia-initiating cells(LICs)initiated the formation of an inflammatory bone marrow stroma,which in turn contributed to inefficiency of osteoblast production by MSCs.At last,we identified an enhanced secretion of the inflammatory cytokine such as Il17 b and Il1f9 or/and inhibited secretion of the anti-inflammatory cytokine such as Pf4 contributed to the remodeling of the niche,which in turn resulted in the leukemia progression.Taken together,our data suggest that the leukemia cells actively remodel the hematopoietic microenvironment by creating a inflammatory milieu,thus providing a favorable environment for leukemia progression that leads to the malignant predominance over normal hematopoiesis.This study provides better understanding of the leukemogenesis and sheds light on the identification of new therapeutic targets for curing AML.