Leveraging clonal competition between CHIP and aggressive malignant clones as a novel therapeutic approach 3155

Description Hematopoietic stem cells (HSC) are in constant competition, as a result variant clones with a fitness advantage emerge with aging resulting in clonal hematopoiesis of indeterminate potential (CHIP). Multiple independent clones can coexist, and potentially come into equilibrium. But, in acute leukemia, a clone overtakes the system inhibiting normal hematopoiesis. We propose that the competitive ability of CHIP clones can be leveraged to dampen expansion of aggressive malignant clones. As proof of principle, we tested if Tet2-/- bone marrow (BM) cells could restrain the expansion of MPLW515L BM cells in an aggressive myeloproliferative neoplasm mouse model. We competitively transplanted BM transduced with GFP-tagged hMPLW515L retrovirus mixed with WBM from WT or Tet2-/- mice. Ten percent of both WT and Tet2-/- groups died by 4 weeks post-transplant. However, surviving mice transplanted with Tet2-/- competitor cells had fewer GFP+ cells in the blood compared to mice transplanted with WT competitor cells (e.g., 23% vs. 55% in WT at day 105). At 5 months post-transplant we sacrificed mice to assess MPLW515L cells in bone marrow and spleen. Mice transplanted with WT competitor cells had more GFP+ cells in HSC compartments and larger spleen and liver weights than those transplanted with Tet2-/- competitor cells. This work suggests that competitive, non-malignant clones like Tet2-/- can buffer malignant clones as a novel therapeutic strategy for aggressive hematologic cancers.