Title

RepSox Slows Decay of CD34+ Acute Myeloid Leukemia Cells and Decreases T Cell Immunoglobulin Mucin‐3 Expression

Document Type

Article

Publication Date

2014

College/Unit

School of Medicine

Department/Program/Center

Pathology, Anatomy and Laboratory Medicine

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.

Source Citation

Jajosky, A. N., Coad, J. E., Vos, J. A., Martin, K. H., Senft, J. R., Wenger, S. L., & Gibson, L. F. (2014). RepSox Slows Decay of CD34+Acute Myeloid Leukemia Cells and Decreases T Cell Immunoglobulin Mucin-3 Expression. STEM CELLS Translational Medicine, 3(7), 836–848. https://doi.org/10.5966/sctm.2013-0193

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