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 ؊ stemcell 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 IntroductionDespite high-dose chemotherapy, only 30% to 40% of patients with acute myeloid leukemia (AML) survive, which is due mainly to relapse of the disease. 1 AML is generally regarded as a stem-cell disease. However, there is debate whether normal stem cells undergoing leukemogenic mutations is the explanation for leukemogenesis. Alternatively, leukemogenic mutations occurring at a later developmental stage, resulting in stem cell-like behavior, might be an alternative or additional option. [2][3][4] For CD34 ϩ AML, several authors have shown that leukemic stem cells are present in the CD34 ϩ CD38 Ϫ compartment. 5,6 It has been proven in vitro that these stem cells are more resistant to chemotherapy, compared with the progenitor CD34 ϩ CD38 ϩ cells. 7 In vivo, after chemotherapy, the residual malignant CD34 ϩ CD38 Ϫ cells are thought to differentiate to a limited extent, producing leukemic cells with an immunophenotype, which usually reflects that at diagnosis. Sensitive techniques allow early detection of small numbers of these differentiated leukemic cells, called minimal residual disease (MRD), which eventually causes relapse of the disease. 8 Since in this concept the stem cell is the origin of MRD and relapse, stem cell-targeted therapy would be of potentially high benefit for AML patients. Moreover, early detection of leukemic stem cells after chemotherapeutic treatment might offer prognostic value in predicting relapse of the disease. Different options for stem-cell identification and/or targeted therapy have been described such as anti-CD123, anti-CD44, and anti-CD33, but all have some (potential) disadvantages, including expression on normal stem cells and/or nonhematologic tissues. [9][10][11] Since the bone marrow of a (chemotherapy-) treated patient cannot be considered normal, it is extremely important to study whether after treatment nor...