By age 70, most people carry clonal hematopoiesis of indeterminate potential (CHIP) — mutant blood stem cell clones, most commonly TET2 or DNMT3A, that expand silently and drive chronic inflammation, cardiovascular disease, and eventual leukemia. No existing therapy shrinks these clones. Senolytics clear senescent cells. Rapamycin slows aging. Neither touches the mutant stem cells already dominating the bone marrow.

The mechanism: TET2-mutant HSPCs overexpress the thrombopoietin receptor Mpl via aberrant H3K79me2 chromatin marks at the Mpl promoter. This gives them a competitive fitness advantage over wild-type stem cells in the aged marrow niche, where inflammatory cytokines (IL-1β, IL-6) further amplify their dominance.

The proposal: a two-phase sequential regimen in aged mice with established TET2-driven clonal hematopoiesis (30–50% mutant chimerism). Phase 1 (weeks 1–4): subcutaneous pinometostat (EPZ-5676, DOT1L inhibitor) via osmotic pump to strip H3K79me2 from the Mpl locus in TET2-mutant HSPCs, normalizing their thrombopoietin receptor expression and eliminating their fitness edge. Phase 2 (weeks 5–16): oral ruxolitinib (JAK2 inhibitor) to block residual JAK/STAT signaling that independently supports mutant clone expansion in the inflammatory aged niche.

The key insight: the sequencing matters. Pinometostat primes the epigenetic reset before ruxolitinib removes the signaling crutch — attacking the upstream driver before blocking the downstream effector. This is repair, not suppression: the mutant clone is stripped of the specific chromatin architecture that differentiates it from wild-type.

Predicted outcomes: ≥40% reduction in TET2-mutant clone frequency by week 12, persisting ≥8 weeks after treatment withdrawal, with <20% decline in wild-type stem cell counts and no cytopenias.

Falsification: if TET2-mutant clones rebound to baseline within 4 weeks of stopping treatment, the epigenetic reset is not durable and the approach fails as a repair strategy. If wild-type HSPCs decline by >30%, the therapeutic window is too narrow for clinical translation.

SENS category: OncoSENS — reversal of somatic mutational damage in hematopoietic stem cells

Key references: • DOT1L-dependent Mpl overexpression in TET2-mutant HSPCs (PMID: 37075253) • Pinometostat pharmacokinetics requiring subcutaneous delivery in mice (PMID: 23810197) • Aged marrow niche selectively advantages TET2-deficient clones (PMID: 29988125)