Grateful for funding support for this work from NIH, EvansMDS & @llsusa.bsky.social

Congrats to Kira Young who spearheaded this work & all contributing authors. This was a fun (and long!) collaboration with @marcmansour.bsky.social, @challenlab.bsky.social, @ericpietras.bsky.social, Kelsey Fisher-Wellman, @keisukeito-lab.bsky.social & Steven Chan

To me, one of the coolest things about these papers is that three different labs in three different countries (US, Canada, UK) INDEPENDENTLY observed the same foundational phenotype of increased mitochondrial OXPHOS in Dnmt3a-mutant hematopoietic stem & progenitor cells 🇨🇦🇬🇧🇺🇸

Together, we report that mitochondrial activity is a targetable mechanism by which clonal hematopoiesis-mutant HSCs gain a selective advantage over wild-type HSCs.

We find that MitoQ also targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-mutant HSCs, supporting species conservation.

Exploiting elevated mitochondrial membrane potential, we used long-chain alkyl-TPP molecules (ex. MitoQ) that selectively accumulate in the mitochondria. These caused reduced mitochondrial respiration, apoptosis, and ablated the competitive advantage of Dnmt3a-mutant HSCs.

Dnmt3a-mutant HSCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional OXPHOS capacity, high
mitochondrial membrane potential & greater dependence on mitochondrial respiration versus wild-type HSCs.

Using a mouse model of Dnmt3a-mutant CH that our lab previously developed, we found that mutant HSCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-induced changes in the bone marrow microenvironment.

Drivers of clonal hematopoiesis include aging and inflammation. How hematopoietic stem cells (HSCs) with somatic mutations gain a selective advantage in these contexts is an unresolved question that we set out to tackle.

Lastly, a shout out to my co-chair Sant-Rayn Pasricha (whom I will nudge onto Bluesky!) for a lot of laughs, for keeping an at-times challenging job light and fun, & for literally sharing the spotlight with me. Wouldn't have wanted to partner with anyone else. Hope to see everyone at #ASH25!

I have learned more about the breadth and depth of the #hematology field than I ever knew before. I also learned that it's near impossible to keep up with social media posts while also having the scientific program co-chair role (my bad!). 5/n

I leave #ASH24 tired (obv!) but inspired. Thank you to the basic scientists, the drug developers, the clinical trialists, the practicing physicians that bring their best science, successes & failures, & unique perspectives to this meeting. 4/n

Behind the scenes, @ash-hematology.bsky.social staff are the most professional, hard-working partners that not only care deeply about hematology but also essential topics of DEI & health advocacy. They make the magic happen. Shout out to Alice Kuaban, Kelly Rose & Patricia Frustace. 3/n

The annual @ash-hematology.bsky.social meeting is a result of dedicated work of many, many brilliant volunteers over 18+ months. Scientific Committees (shout out to the chairs!), abstract reviewers, Committee for Scientific Affairs, Program Committee, Executive Committee. It's amazing. 2/n