CAR T-cell therapy for AML ideally targets LSCs and AML blasts, but spares HSCs and myelopoiesis. Early approaches such as targeting of CD123 (a) and CD33 (b) did not spare HSCs or myelopoiesis, resulting in aplasia. (c) More complex targeting approaches where CAR T activation is triggered only by the presence of 2 antigens can allow increased specificity. In this example, CD13 is expressed by LSC and blasts, but it is also expressed by HSCs and myeloid cells. Although TIM3 is expressed outside the hematopoietic system, it is expressed on AML cells but not on normal HSCs. (d) Finally, some antigens such as Siglec-6, which are expressed on AML cells but not on normal hematopoietic cells may allow simple and selective targeting of AML.