Hematopoietic stem and progenitor cells in experimental remission model of acute myeloid leukemia in vivo [ATAC-seq]

Inflammation is a hallmark of cancer and is linked to patient prognosis in acute myeloid leukemia (AML). Our recent study revealed that hematopoietic stem and progenitor cells (HSPCs) exhibit an inflammatory active state and serve as a cellular source of inflammatory cytokine secretion in AML. Recent studies in infection and chronic inflammation related disease models have revealed that inflammation can reprogram HSPCs to fuel chronic inflammation related co-mobidities. Building on our report of AML-associated inflammation in HSPCs, here we ask whether AML-experienced normal HSPCs are reprogrammed in AML. To investigate this, we utilized a chimeric model of AML, carrying both doxycycline-inducible leukemic and healthy wildtype hematopoietic fractions, to generate an AML remission model. To test whether AML-experienced HSPCs harbor inflammatory memory, mice were challenged with heterogenous inflammatory activation. Our transcriptomic and epigenetic results show for the first time that phenotypically normal, AML-experienced HSPCs carry a durable inflammatory memory whereby primary exposure to AML secreted factors alters their response to secondary stimuli. Our finding suggests that AML-experienced HSPCs are innate immune reprogrammed in the AML niche.