CD33 as a potential AML stem cell-associated antigen

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It has long been recognized that AML encompasses functionally diverse cells, and disease origination from a leukemic stem cell was first suspected many decades ago (57). Despite intense efforts, however, the cellular origin of AML remains unclear, with ongoing dispute as to whether these leukemias arise from transformed hematopoietic stem cells or emerge as a result of genetic events occurring in more mature progenitor cells (57-62). Regardless of this controversy, the impetus to pursue CD33 as therapeutic target emanated not from the fact that blasts of the vast majority of AML patients express CD33 but from the early notion that some AMLs may predominantly or entirely involve committed CD33⁺ myeloid precursors, suggesting that this antigen could serve to eradicate underlying malignant stem cells in such leukemias (58). Specifically, classic studies on X chromosome inactivation patterns showed clonal dominance in multiple cell lineages (granulocytes, monocytes, erythrocytes, platelets, and occasionally B lymphocytes) in some leukemias, reflecting origination and expansion at the level of pluripotent CD33^- hematopoietic stem cells. In others, clonal dominance was limited to granulocytes and monocytes, suggesting that expansion of the malignant clone could occur at the committed CD33⁺ myeloid precursor cell stage (63, 64); an example for the latter may be acute promyelocytic leukemia (APL), as small studies indicate that this disease is mainly expressed in granulocytes/monocytes and predominantly involves CD33⁺ precursors (65). In these “mature” leukemias, it was hypothesized that CD33^- precursors would be predominantly or completely normal. To test this assumption, CD33⁺ cells were removed in vitro via CD33-directed complement-mediated lysis or fluorescence-activated cell sorting in a small number of patients with such leukemias and the remaining CD33^- cells were placed in long-term culture together with irradiated allogeneic stroma cells (66, 67). Over time, CD33^- precursors from some patients indeed generated colony-forming cells with X chromosome inactivation patterns consistent with predominantly non-clonal hematopoiesis (66, 67). These seminal observations provided the scientific basis for the development and clinical testing of CD33-targeted therapy as a stem cell-directed treatment in a subset of AMLs