In this study, we identify CLL-1, which has a favorable “on-target off-tumor” toxicity profile, as a promising candidate for cellular therapy targeting JMML, and we report that CLL1CART have potent in vitro and in vivo effector functions against primary human JMML cells, including LSCs, as evidenced by lower secondary transplantability in vivo of CLL1CART-treated cells compared to appropriate controls. Here, PTPN11 is linked to neoplasm.