Haematopoietic stem cells (HSC) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory ‘emergency’ signal, directly accelerates cell division and myeloid differentiation of HSCs via precocious activation of a PU.1-dependent gene program. While this effect is essential for rapid myeloid recovery following acute injury to the bone marrow (BM), chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges like transplantation. Importantly, these damaging effects are transient and fully reversible upon IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and likely underlies deregulated blood homeostasis in chronic inflammation conditions.

Quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure

The malignant transformation of normal cells is driven by both genetic and epigenetic changes. With the advent of next-generation sequencing and large-scale multinational consortium studies, it has become possible to profile the genomes and epigenomes of thousands of primary tumors from nearly every cancer type. From these genome-wide studies, it became clear that the dynamic regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression. Proper control of DNA methylation is not only crucial for regulating gene transcription, but its broader consequences include maintaining the integrity of the genome and modulating immune response. Here, we describe the aberrant DNA methylation changes that take place in cancer and how they contribute to the disease phenotype. Further, we highlight potential clinical implications of these changes in the context of prognostic and diagnostic biomarkers, as well as therapeutic targets.