repsox and Leukemia--Myeloid--Acute

Despite initial response to therapy, most acute myeloid leukemia (AML) patients relapse. To eliminate relapse-causing leukemic stem/progenitor cells (LPCs), patient-specific immune therapies may be required. In vitro cellular engineering may require increasing the "stemness" or immunogenicity of tumor cells and activating or restoring cancer-impaired immune-effector and antigen-presenting cells. Leukapheresis samples provide the cells needed to engineer therapies: LPCs to be targeted, normal hematopoietic stem cells to be spared, and cancer-impaired immune cells to be repaired and activated. This study sought to advance development of LPC-targeted therapies by exploring nongenetic ways to slow the decay and to increase the immunogenicity of primary CD34(+) AML cells. CD34(+) AML cells generally displayed more colony-forming and aldehyde dehydrogenase activity than CD34(-) AML cells. Along with exposure to bone marrow stromal cells and low (1%-5%) oxygen, culture with RepSox (a reprogramming tool and inhibitor of transforming growth factor-β receptor 1) consistently slowed decline of CD34(+) AML and myelodysplastic syndrome (MDS) cells. RepSox-treated AML cells displayed higher CD34, CXCL12, and MYC mRNA levels than dimethyl sulfoxide-treated controls. RepSox also accelerated loss of T cell immunoglobulin mucin-3 (Tim-3), an immune checkpoint receptor that impairs antitumor immunity, from the surface of AML and MDS cells. Our results suggest RepSox may reduce Tim-3 expression by inhibiting transforming growth factor-β signaling and slow decay of CD34(+) AML cells by increasing CXCL12 and MYC, two factors that inhibit AML cell differentiation. By prolonging survival of CD34(+) AML cells and reducing Tim-3, RepSox may promote in vitro immune cell activation and advance development of LPC-targeted therapies.

Topics: Aldehyde Dehydrogenase; Antigens, CD34; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Cellular Reprogramming; Chemokine CXCL12; Coculture Techniques; Dose-Response Relationship, Drug; Feeder Cells; Gene Expression Regulation, Leukemic; Hepatitis A Virus Cellular Receptor 2; Humans; Leukapheresis; Leukemia, Myeloid, Acute; Membrane Proteins; Neoplastic Stem Cells; Oxygen; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyridines; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; T-Lymphocytes; Time Factors; Tumor Cells, Cultured; Tumor Escape