Blocking PRMT7 to target leukemia stem cells in CML

Inhibiting the methyltransferase PRMT7 could treat tyrosine kinase inhibitor-resistant CML by disrupting self-renewal of leukemic stem cells. In a mouse model of BCR-ABL-driven CML, hematopoietic stem cell (HSC)-specific knockout of PRMT7 increased survival, delayed tumor growth, and decreased tumor burden, splenomegaly, lung hemorrhaging and leukemic stem cell populations in the bone marrow and spleen, without disrupting normal hematopoiesis.

Design and synthesis of a small molecule PRMT7 inhibitor yielded a compound that bound PRMT7 with a K_D of 5 μM and inhibited PRMT7 in vitro with an IC₅₀ of 5 μM. In cultures of patient-derived CD34⁺ cells, including cells from a patient resistant to Gleevec imatinib, the compound decreased PRMT7 activity and leukemic stem cell renewal and increased tumor cell apoptosis without affecting the survival and renewal of normal CD34⁺ cells. In the CML mouse model, the compound increased median survival and decreased splenomegaly and lung hemorrhaging without affecting normal HSCs. In two patient-derived xenograft mouse models of CML, the compound decreased CML engraftment in the bone marrow and spleen...