Juvenile myelomonocytic leukemia stem cells are sensitive to NK cell-mediated lysis and express targetable antigens Open Access

• JMML is comprised by distinct subpopulations, and the regenerating leukemic stem cell population represents an important therapeutic target.

• Natural killer cells have the ability to eliminate leukemic stem cells, and LSCs express antigens that may be targeted via cell therapy.

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm for which hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Innovative therapies are needed to address high rates of morbidity, treatment-related mortality, and relapse. Monoclonal antibodies and adoptive cell transfer of natural killer (NK) cells or T cells are approved or being investigated for other myeloid leukemias; however, their activity against JMML has not been reported. In the present study, we hypothesized that NK cells may effectively target JMML tumor cells. Mass cytometry was employed to evaluate the expression of NK cell activating and inhibitory ligands and candidate target antigens on the monocytic and stem cell subsets of JMML. Monocytes from healthy donors and monocytic subsets of JMML were similar in NK cell ligand expression, and JMML monocytes were resistant to NK cell cytotoxicity in vitro. However, NK cells effectively controlled proliferation of JMML colony-forming cells. CD34⁺CD38^– JMML stem cells express a broad repertoire of NK cell ligands similar to that of acute myeloid leukemia stem cells, and CD33, CD44, and CD47 were expressed by both CD34⁺CD38^- stem cells and CD34⁺CD38⁺ progenitors in JMML. This suggests that JMML may be responsive to NK cell-mediated activity, and that targeting CD33, CD44, or CD47 may facilitate eradication of JMML.