Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis

Area of Science:

• Hematology
• Aging Research
• Stem Cell Biology

Background:

• Fatty bone marrow (FBM) and somatic mutations in hematopoietic stem cells (HSCs), known as clonal hematopoiesis (CH), increase with age.
• The interaction between FBM and CH evolution is not well understood.

Purpose of the Study:

• To investigate the influence of FBM on the development of CH.
• To explore the mechanisms underlying this interaction.

Main Methods:

• Utilized two preclinical male mouse models (sub-lethal irradiation and castration).
• Employed an adipogenesis inhibitor (PPARγ inhibitor) as a control.
• Performed single-cell RNA-sequencing on rodent HSCs.
• Conducted cytokine analysis of bone marrow (BM) fluid and BM-derived adipocytes.
• Used anti-IL-6 neutralizing antibodies.

Main Results:

• FBM significantly increased self-renewal of DNMT3A-mutated HSCs (DNMT3A^Mut-HSCs) in both human and rodent models.
• Older mice with FBM showed even higher self-renewal in their DNMT3A^Mut-HSCs.
• FBM exposure led to a 6-10 fold increase in DNMT3A^Mut-HSCs and activated inflammatory signaling.
• Increased IL-6 levels were observed in FBM conditions.
• Blocking IL-6 significantly reduced the selective advantage of DNMT3A^Mut-HSCs.

Conclusions:

• Paracrine inflammatory signals from FBM promote DNMT3A-driven clonal hematopoiesis.
• The IL-6 pathway plays a critical role in mediating this effect.
• Inhibiting the IL-6 pathway offers a potential strategy to counteract FBM-induced CH.