The novel AML stem cell-associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells

In CD34⁺ acute myeloid leukemia (AML), the malignant stem cells reside in the CD38⁺ compartment. We have shown before that the frequency of such CD34⁺CD38^- cells at diagnosis correlates with minimal residual disease (MRD) frequency after chemotherapy and with survival. Specific targeting of CD34⁺CD38⁺ cells might thus offer therapeutic options. Previously, we found that C-type lectin-like molecule-1 (CLL-1) has high expression on the whole blast compartment in the majority of AML cases. We now show that CLL-1 expression is also present on the CD34⁺CD38^- stem-cell compartment in AML (77/89 patients). The CD34⁺CLL-1⁺ population, containing the CD34 ⁺CD38^-CLL-1⁺ cells, does engraft in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with outgrowth to CLL-1⁺ blasts. CLL-1 expression was not different between diagnosis and relapse (n = 9). In remission, both CLL-1^- normal and CLL-1 ⁺ malignant CD34⁺CD38^- cells were present. A high CLL-1⁺ fraction was associated with quick relapse. CLL-1 expression is completely absent both on CD34⁺CD38^- cells in normal (n = 11) and in regenerating bone marrow controls (n = 6). This AML stem-cell specificity of the anti-CLL-1 antibody under all conditions of disease and the leukemia-initiating properties of CD34⁺CLL-1⁺ cells indicate that anti-CLL-1 antibody enables both AML-specific stem-cell detection and possibly antigen-targeting in future.