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

Jennifer M Grants1, Joanna Wegrzyn1, Tony Hui2

  • 1Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

Blood
|May 9, 2020
PubMed

Insights

Loss of miR-146a drives aging-related inflammation and myeloid malignancy by impairing hematopoietic stem cell function. Restoring inflammatory balance can restore stem cell function and reduce cancer incidence.

Area of Science:

  • Hematology
  • Immunology
  • Aging Research

Background:

  • Aging causes hematopoietic system changes, including inflammation and impaired stem cell function, increasing myeloid malignancy risk.
  • Inflammaging is implicated in age-related stem cell dysfunction and cancer, but underlying mechanisms are unclear.
  • Loss of microRNA-146a (miR-146a) is linked to aging-associated inflammation in acute myeloid leukemia (AML).

Purpose of the Study:

  • To investigate the role of miR-146a in age-related hematopoietic stem cell (HSC) dysfunction and myeloid malignancy.
  • To elucidate the mechanisms by which miR-146a loss contributes to inflammaging and HSC impairment.
  • To determine if targeting inflammation can mitigate HSC dysfunction and reduce malignancy in the absence of miR-146a.

Main Methods:

  • Utilized aged wild-type and young miR-146a-null mice models.
  • Employed single-cell assays to assess HSC quiescence, stemness, differentiation potential, and epigenetic state.
  • Conducted DNA methylation and transcriptome profiling.
  • Investigated the effects of targeting IL6 and TNF signaling.

Main Results:

  • miR-146a expression declines with age, and its loss accelerates HSC aging and inflammation in young mice.
  • Loss of miR-146a depletes primitive, quiescent HSCs and alters HSC function and epigenetic state.
  • Inflammatory signaling pathways (NF-κB, IL6, TNF) are implicated in HSC dysfunction, creating a self-sustaining inflammatory loop.
  • Targeting IL6 or TNF restored HSC function, reduced malignancy incidence in miR-146a-null mice, and highlighted increased HSC sensitivity to IL6.

Conclusions:

  • Loss of miR-146a is a key driver of HSC inflammaging and myeloid malignancy through both cell-extrinsic and cell-intrinsic mechanisms.
  • Restoring inflammatory balance by targeting IL6 or TNF can ameliorate HSC dysfunction and reduce cancer risk.
  • miR-146a plays a critical role in maintaining HSC function and preventing age-related myeloid malignancies.

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