To evaluate whether HMA therapy can decrease the mutational burden in the HSPC populations, we generated different chimeric mouse models carrying four of the most frequent founder mutations identified in MDS (Extended Data Fig. 4a) by competitively transplanting lethally irradiated CD45.1+ wild-type (WT) recipient mice with CD45.2+Vav1 (Vav)-Cre/Tet2L/L, Mx1-Cre/Srsf2P95H, U2AF1S34F/rtTA or Mx1-Cre/Runx1L/L/Srsf2P95H cells and CD45.1+ WT BM cells (Supplementary Fig. 6f). Here, MX1 is linked to myelodysplastic syndrome.