Target for Leukemia Stem Cells
Acute myeloid leukemia (AML) is a disorder of malignant stem cells with an unlimited capacity for self-renewal. Surprisingly for an epithelial associated protein, MUC1 is expressed on AML CD34+/lineage-/CD38- stem cells as compared to their normal stem cell counterparts. In contrast to normal CD34+/CD38- cells, upregulation of MUC1 expression is detectable on primary AML cells isolated from multiple patients (Fig. 1). MUC1 expression is not restricted to AML CD34+ populations, as similar results were obtained with leukemic cells from patients with CD34- disease.
AML cells from 20 patients with CD34+ active disease were analyzed by flow cytometry for MUC1 expression on CD34+/lineage-/CD38- and CD34+/lineage-/CD38+ populations. Each symbol represents the individual patients. Peripheral blood stem cells from 7 normal donors and bone marrows from 3 patients with lymphoid malignancies without evidence of tumor involvement were also analyzed for MUC1 expression as controls. The results are expressed as the percentage of cells that are MUC1+ with the horizontal bars representing the mean percentage of MUC1 expression for the different groups.
Significantly, AML stem cell populations that highly express MUC1 (MUC1high) engrafted with the development of leukemia in NSG immunodeficient mice. In contrast, MUC1low populations established normal hematopoiesis in the NSG model. Blocking function of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but had no significant effect on normal hematopoietic cell engraftment, supporting the dependence of the AML stem cell population on MUC1-C for survival.
Figure 2 shows a statistically significant decrease in established AML in the bone marrows from the GO-203-treated mice as compared with that obtained for the PBS-treated mice.
In summary, there is strong evidence that MUC1 is highly expressed in AML stem cells as compared to their normal counterparts and that MUC1-C is a selective target for the treatment of AML in the engrafted NSG mouse model. Currently, GO-203 is under clinical evaluation in a Phase 2 clinical trial in combination with decitabine for patients with relapsed/refractory acute myeloid leukemia (AML).