Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors

Abstract

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.

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

“…Hence, deficiency in key myeloid regulators, like PU.1, related to indirect effects of mutations in other genes may serve as a crucial nexus that primes HSCs to activate aberrant protein synthesis and cell cycle activity when triggered by inflammatory signals associated with BM pathogenesis, like IL-1 and TNF-α. This model is illustrated by a parallel study by our group in which we found that IL-1 can trigger the selective expansion of Cebpa -deficient HSPCs in a mouse model of oncogenic BM competition ( Higa et al, 2021 ). These findings are consistent with the theory of adaptive oncogenesis, which stipulates that environmental factors associated with tissue decline, such as inflammation, are crucial drivers of oncogenesis by selecting for emergent phenotypes, such as increased proliferation, self-renewal, or survival, that are linked cancer-associated mutations ( Henry et al, 2015 ; Laconi et al, 2020 ).…”

Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection

“…On the other hand, PU.1 -deficient HSCs are largely insensitive to this effect of IL-1, fail to repress Myc , and instead continue to proliferate and expand in the BM ( Chavez et al, 2021 ) during IL-1 exposure. Likewise, Cebpa -deficient MPPs can outcompete their WT counterparts in vivo when exposed to chronic IL-1 ( Higa et al, 2021 ). Strikingly, both PU.1 - and Cebpa- deficient HSPCs are not selected for in the absence of the inflammatory signal, providing important evidence that the loss of these factors alone is not sufficient to promote their expansion.…”

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

“…Inflammatory signals activate HSC and promote myelopoiesis [37,75,[83][84][85]92]. This response is beneficial in combatting infection, but chronic exposure to inflammatory insults impairs HSC self-renewal and causes stem cell loss.…”

“…C/EBPβ is required for LPSinduced memory, which improves myeloid differentiation and the resistance to secondary infection [94]. The loss of C/EBPβ attenuates an IL-1β-driven myeloid gene program and expands hematopoietic stem and progenitor cells (HSPCs) [92]. It also has been shown that the induction of myeloid differentiation by IL-1β and TNF-α is likely due to the activation of PU.1 [36,82,93] and mice lacking the PU.1 upstream regulatory severely attenuated myeloid differentiation.…”