Presenting Author Nemours Childrens Health Wilmington, Delaware
Pediatric acute myeloid leukemia (AML) is characterized by the malignant transformation of hematopoietic stem and progenitor cells that lead to the accumulation of immature myeloid cells in the bone marrow. Standard treatment of AML includes intense cytotoxic chemotherapy and hematopoietic stem cell transplants with relatively low cure rates. Targeted therapy options for AML are limited. Mesothelin (MSLN) is a 40-kDa glycosylphosphatidylinositol (GPI)-anchored protein that is highly expressed on many tumors, but lacks expression in many normal tissues, making it an excellent target for cancer therapies. More recently, the identification of MSLN expression in a subset (about one-third) of pediatric AML patients warranted preclinical studies with MSLN-targeted therapies, including immunotherapy. Recently, our lab utilized bispecific T cell engaging antibodies to recruit T cells to MSLN-expressing leukemic cells, increasing in vivo survival rates in patient-derived xenograft models.
MSLN has been shown to play a role in promoting proliferation and invasion in mesothelioma, ovarian cancer, and pancreatic adenocarcinoma, mainly through interactions with MUC16/CA125. Current investigative efforts in AML focus on MSLN-targeted therapies, while the function of MSLN in AML remains unresolved. Previously, we identified a correlation between MSLN expression and extramedullary disease, as well as enhanced leukemic burden in xenograft models. Here, we report that MSLN expression is associated with increased rates of cell proliferation and migration.
The proliferation rate of MSLN-negative AML cell lines, MV4;11 amp; NOMO-1-KO, and two MSLN-expressing cell lines, MV4;11-MSLN amp; NOMO-1, was evaluated by BrDU proliferation assay or direct measurement of cell numbers over 96 hours. MSLN-expressing cells proliferated at an increased rate comparative to the non-expressing cells. Consistent with higher proliferation rate in MSLN-expressing cells, these cells showed reduced percentage of G1 population and increased population in the S phase of the cell cycle. In a Transwell migration assay, higher number of MV4;11-MSLN cells migrated towards serum compared to their wild-type counterpart, indicating that MSLN expression promoted cell migration. Our data suggest that MSLN expression in pediatric AML cells enhances proliferation and migration. Therefore, targeting MSLN may be beneficial to curb AML progression.
Leukemia Research Foundation of Delaware, Lisa Dean Moseley Foundation, Andrew McDonough B+ Foundation, Nemours Foundation, Delaware INBRE.
