DUX4-r ALL is susceptible to killing by CAR T cells directed against the myeloid–associated marker CD371. (A) Cell surface marker CD371 expression in BCP-ALL blast cells and residual nonleukemic hematopoiesis as determined by scADT-seq. (B) Open chromatin in the gene region of the CLEC12A gene (that encodes CD371) is visualized in BCP-ALL blast cells and other cell types. (C) Schematic illustration of targeting of DUX4-r ALL blast cells expressing CD371 and CD19 on the cell surface by CD19 and CD371 CAR T cells, respectively. (D) Coincubation with wild-type NALM6 displayed antitumor activity against CD371 and CD19 CAR T cells. Only CD19 CAR T cells retained the cytotoxic activity in NALM6-CD371-KO lacking CD371 expression. (E) Effective ex vivo targeting of DUX4-r ALL blast cells in 3 independently derived DUX4-r PDX samples. The proportion of live PDX cells after CAR T cell treatment. (F) Experimental design for in vivo targeting of the DUX4-r-13 PDX sample in immunodeficient mice using CD371-CAR (44544) T cells, CD19-CAR T cells, or untransduced T cells. (G) The number of human DUX4-r blast cells (ALL cells) in BM at the end point. (H) Number of human DUX4-r blast cells (ALL cells) in PB at the end point. (I) Spleen weight at the end point. PB, peripheral blood.