Leukemia confers a durable imprint on healthy hematopoietic stem and progenitor cells

Abstract

Recent models of infection and experimental inflammation reveal that hematopoietic stem and progenitor cells (HSPCs) can generate a memory of the exposure. While the acute inflammatory activity rapidly resolves, cells acquire a heightened capacity to respond to subsequent stimulation. Inflammation is also a constitutive feature of cancer, including hematologic malignancies. Here, we adapt a translationally relevant model of acute myeloid leukemia (AML) to determine if inflammation in the bone marrow (BM) niche durably reprograms resident healthy HSPCs. To simulate the onset of malignancy and the subsequent remission, we generated hematopoietic chimera composed of healthy HSPCs and HSPCs bearing an inducible oncogenic human MLL-AF9 translocation expression cassette, a validated model of AML. Results show that the exposure to AML blasts in the BM leaves healthy HSPCs with transcriptomic changes and a shift to glycolytic metabolism during experimental remission. A secondary challenge of AML-experienced animals results in gene expression changes in inflammatory and metabolic pathways. These modified responses coincide with altered chromatin accessibility in AML-experienced HSPCs. Altogether, our observations provide first evidence for the durable inflammatory reprogramming of healthy HSPCs in the cancer microenvironment.