Understanding clonal hematopoiesis and initiation of myeloid malignancies

Clonal hematopoiesis often precedes the development of myeloid malignancies, but a majority of these individuals do not develop leukemia. Little is known of this tumor evolution.

We propose to study the transition from clonal hematopoiesis to leukemia, focusing on the immature preleukemic stem cells containing only the initiating mutations.

We will use primary patient samples from distinct evolutionary stages of disease development and leverage our recently developed protocol for single cell RNA sequencing with high fidelity genotyping (Landberg et al BCD 2024).

This will allow direct comparison of mutant and wildtype cells within the same individual for a previously unattainable level of fidelity.

Complementary characterization of cell surface expression and epigenetic alterations will be performed as samples are collected from healthy donors, individuals with clonal hematopoiesis, myelodysplastic syndrome, and acute myeloid leukemia with mutations in the epigenetic regulators IDH1, IDH2, and TET2.

We will explore the transcriptomic, epigenetic, and proteomic disease specific features to allow FACS-isolation of wildtype and mutant cells from the same individual for direct in vitro treatment experiments of targetable vulnerabilities.

We expect the results of these experiments to further our understanding of preleukemic conditions and facilitate the development of targeted therapies potentially capable of preventing initiation as well as relapse of myeloid malignancies.