Open AccessChronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors
Author(s) -
Kelly Higa,
Andrew Goodspeed,
James Chavez,
Marco De Dominici,
Etienne Danis,
Vadym Zaberezhnyy,
Jennifer L. Rabe,
Daniel G. Tenen,
Eric M. Pietras,
James DeGregori
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20200560
Subject(s) - cebpa , haematopoiesis , biology , progenitor cell , myeloid , cancer research , immunology , inflammation , myelopoiesis , proinflammatory cytokine , stem cell , hematopoietic stem cell , microbiology and biotechnology , genetics , mutation , gene
The early events that drive myeloid oncogenesis are not well understood. Most studies focus on the cell-intrinsic genetic changes and how they impact cell fate decisions. We consider how chronic exposure to the proinflammatory cytokine, interleukin-1β (IL-1β), impacts Cebpa-knockout hematopoietic stem and progenitor cells (HSPCs) in competitive settings. Surprisingly, we found that Cebpa loss did not confer a hematopoietic cell–intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection for Cebpa loss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-knockout HSPCs are resistant to the prodifferentiative effects of chronic IL-1β, and competitively expand. We further show that ectopic CEBPA expression reduces the fitness of established human acute myeloid leukemias, coinciding with increased differentiation. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.