Altered microRNA expression links IL6 and TNF-induced inflammaging with myeloid malignancy in humans and mice

Blood. 2020 Jun 18;135(25):2235-2251. doi: 10.1182/blood.2019003105.


Aging is associated with significant changes in the hematopoietic system, including increased inflammation, impaired hematopoietic stem cell (HSC) function, and increased incidence of myeloid malignancy. Inflammation of aging ("inflammaging") has been proposed as a driver of age-related changes in HSC function and myeloid malignancy, but mechanisms linking these phenomena remain poorly defined. We identified loss of miR-146a as driving aging-associated inflammation in AML patients. miR-146a expression declined in old wild-type mice, and loss of miR-146a promoted premature HSC aging and inflammation in young miR-146a-null mice, preceding development of aging-associated myeloid malignancy. Using single-cell assays of HSC quiescence, stemness, differentiation potential, and epigenetic state to probe HSC function and population structure, we found that loss of miR-146a depleted a subpopulation of primitive, quiescent HSCs. DNA methylation and transcriptome profiling implicated NF-κB, IL6, and TNF as potential drivers of HSC dysfunction, activating an inflammatory signaling relay promoting IL6 and TNF secretion from mature miR-146a-/- myeloid and lymphoid cells. Reducing inflammation by targeting Il6 or Tnf was sufficient to restore single-cell measures of miR-146a-/- HSC function and subpopulation structure and reduced the incidence of hematological malignancy in miR-146a-/- mice. miR-146a-/- HSCs exhibited enhanced sensitivity to IL6 stimulation, indicating that loss of miR-146a affects HSC function via both cell-extrinsic inflammatory signals and increased cell-intrinsic sensitivity to inflammation. Thus, loss of miR-146a regulates cell-extrinsic and -intrinsic mechanisms linking HSC inflammaging to the development of myeloid malignancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aging / genetics*
  • Aging / immunology
  • Animals
  • Cell Differentiation
  • Cell Self Renewal
  • Cellular Senescence
  • Cytokines / biosynthesis
  • DNA Methylation
  • Female
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Inflammation / genetics*
  • Inflammation / physiopathology
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / physiology*
  • Leukemia, Myeloid, Acute / etiology*
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Middle Aged
  • NF-kappa B / physiology
  • Single-Cell Analysis
  • Transcriptome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / physiology*
  • Young Adult


  • Cytokines
  • IL6 protein, human
  • Interleukin-6
  • MIRN146 microRNA, human
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • NF-kappa B
  • Tumor Necrosis Factor-alpha