“Modeling Clonal Hematopoiesis and Genetic Correction in RUNX1-FPD Using Human iPSC-derived HSCs”

Dr. Papapetrou and her team will develop novel human iPSC-based in vivo models of RUNX1-FPD to investigate mechanisms driving clonal hematopoiesis and progression toward myeloid malignancy. This work leverages the recently published Ng/Elefanty protocol (Nature Biotechnology, 2025), which for the first time enables the derivation of long-term multilineage engrafting hematopoietic stem cells from human iPSCs.

Using isogenic single- and double-mutant iPSC lines in competitive transplantation models, the team will examine how secondary TET2 and ASXL1 mutations influence clonal fitness in RUNX1-FPD and whether inflammatory pathway modulation with FDA-approved agents, including IL-1R, TNFα, and IL-6R blockade, can mitigate expansion of high-risk clones.

A second line of investigation will use three independent pairs of CRISPR/Cas9-corrected and uncorrected patient-derived iPSC lines to define the relative clonal fitness of corrected versus mutant HSCs in vivo, a critical determinant of the feasibility of ex vivo and in vivo gene-correction strategies for RUNX1-FPD.