3061 – PU.1 ENFORCES QUIESCENCE AND LIMITS HEMATOPOIETIC STEM CELL EXPANSION DURING CHRONIC INFLAMMATION

Abstract

Hematopoietic stem cell (HSC) quiescence supports lifelong blood regeneration and guards against pre-leukemic clonal expansion. Acute exposure to the pro-inflammatory cytokine interleukin (IL)-1 drives myeloid cell production and HSC cell cycle entry. However, HSC return to a quiescent state suggesting the presence of a ‘braking' mechanism that limits HSC proliferative capacity during chronic inflammation. To identify mechanism(s) regulating HSC cell cycle activity, we injected mice with IL-1 for 20 days modeling chronic inflammation in vivo. RNA-seq analysis of HSC following IL-1 exposure revealed repression of cell cycle and protein synthesis genes, suggesting the activation of a ‘growth arrest' gene program. This gene program coincided with increased PU.1 expression, and ChIP-seq analysis identified PU.1 binding on nearly all repressed genes, suggesting PU.1 enforces HSC quiescence during chronic inflammation. Strikingly, HSC from IL-1 treated PU.1-deficient mice exhibited loss of quiescence associated with aberrant myeloid expansion in the bone marrow and spleen. Together, our results suggest PU.1 induction maintains HSC quiescence under chronic inflammatory stress. They also suggest IL-1 may confer a competitive advantage to HSC with impaired PU.1 function, triggering aberrant proliferation and myeloid expansion. Several oncogenic mutations found in acute myelogenous leukemia (AML) impair the expression and/or function of PU.1. As AML pre-dominantly affects elderly individuals and leukemogenesis is often associated with chronic inflammation, our data supports a model where chronic inflammation triggers the selective expansion of HSC harboring oncogenic mutations, leading to a pre-leukemic state. Thus, blockade of inflammation may be a tractable approach to delay and/or prevent leukemia.