RepSox slows decay of CD34+ acute myeloid leukemia cells and decreases T cell immunoglobulin mucin-3 expression.

Abstract

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.

• Authors: Audrey N Jajosky, James E Coad, Jeffrey A Vos, Karen H Martin, Jamie R Senft, Sharon L Wenger, Laura F Gibson
• Journal: Stem cells translational medicine (Stem Cells Transl Med) Vol. 3 Issue 7 Pg. 836-48 (Jul 2014) ISSN: 2157-6564 [Print] England
• PMID: 24855276 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©AlphaMed Press.

Chemical References

• Antigens, CD34
• Biomarkers, Tumor
• CXCL12 protein, human
• Chemokine CXCL12
• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• MYC protein, human
• Membrane Proteins
• Proto-Oncogene Proteins c-myc
• Pyrazoles
• Pyridines
• Receptors, Transforming Growth Factor beta
• RepSox
• Aldehyde Dehydrogenase
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• Oxygen

Topics

• Aldehyde Dehydrogenase (metabolism)
• Antigens, CD34 (genetics, metabolism)
• Biomarkers, Tumor (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cellular Reprogramming (drug effects)
• Chemokine CXCL12 (genetics, metabolism)
• Coculture Techniques
• Dose-Response Relationship, Drug
• Feeder Cells
• Gene Expression Regulation, Leukemic (drug effects)
• Hepatitis A Virus Cellular Receptor 2
• Humans
• Leukapheresis
• Leukemia, Myeloid, Acute (genetics, immunology, metabolism, pathology, therapy)
• Membrane Proteins (genetics, metabolism)
• Neoplastic Stem Cells (drug effects, immunology, metabolism, pathology)
• Oxygen (metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism, pathology)
• Time Factors
• Tumor Cells, Cultured
• Tumor Escape