Aug 20, 2014

Chronic Interleukin-1 exposure triggers selective expansion of Cebpa-deficient multipotent hematopoietic progenitors

bioRxiv
Michael ManhartJames DeGregori

Abstract

The early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1; (IL-1), impacts Cebpa-deficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found that Cebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1; exposure engendered potent selection for Cebpa loss. Chronic IL-1; augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1, and competitively expand. 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.

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Mentioned in this Paper

Metabolic Process, Cellular
Study
Protein Binding
Cellular Process
Genes
Regulation of Biological Process
High Throughput Screening
Gene Expression
Protein-Protein Interaction
Biophysics

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