Graft-versus-leukemia (GVL) against mouse blast-crisis chronic myelogenous leukemia (BC-CML) and chronic-phase chronic myelogenous leukemia (CP-CML): shared mechanisms of T cell killing, but programmed death ligands render CP-CML and not BC-CML GVL resistant
Autor: | Srividhya Venkatesan, Warren D. Shlomchik, Julia Chang, Jovana Pavisic, Catherine Matte-Martone, Hung Sheng Tan, Ioanna Athanasiadis |
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Rok vydání: | 2011 |
Předmět: |
Graft-vs-Leukemia Effect
Oncogene Proteins Fusion T cell T-Lymphocytes Immunology Graft vs Leukemia Effect Biology Genes abl Major histocompatibility complex Chronic phase chronic myelogenous leukemia Article Myelogenous Mice immune system diseases Transduction Genetic hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive medicine Immunology and Allergy Animals Humans neoplasms Homeodomain Proteins Mice Knockout Mice Inbred BALB C medicine.disease Nuclear Pore Complex Proteins Leukemia medicine.anatomical_structure surgical procedures operative Retroviridae biology.protein Cancer research Bone marrow Apoptosis Regulatory Proteins Blast Crisis Chronic myelogenous leukemia |
Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 187(4) |
ISSN: | 1550-6606 |
Popis: | Graft-versus-leukemia (GVL) against chronic-phase chronic myelogenous leukemia (CP-CML) is potent, but it is less efficacious against acute leukemias and blast-crisis chronic myelogenous leukemia (BC-CML). The mechanisms underlying GVL resistance are unknown. Previously, we found that alloreactive T cell targeting of GVL-sensitive bcr-abl–induced mouse CP-CML (mCP-CML) required TCR–MHC interactions and that multiple and redundant killing mechanisms were in play. To better understand why BC-CML is resistant to GVL, we performed a comprehensive analysis of GVL against mouse BC-CML (mBC-CML) induced by the retroviral transfer of the bcr-abl and NUP98/HOXA9 fusion cDNAs. Like human BC-CML, mBC-CML was GVL resistant, and this was not due to accelerated kinetics or a greater leukemia burden. To study T cell recognition and killing mechanisms, we generated a panel of gene-deficient leukemias by transducing bone marrow from gene-deficient mice. T cell target recognition absolutely required that mBC-CML cells express MHC molecules. GVL against both mCP-CML and mBC-CML required leukemia expression of ICAM-1. We hypothesized that mBC-CML would be resistant to some of the killing mechanisms sufficient to eliminate mCP-CML, but we found instead that the same mechanisms were effective against both types of leukemia, because GVL was similar against wild-type or mBC-CML genetically lacking Fas, TRAIL-R, Fas/TRAIL-R, or TNFR1/R2 or when donor T cells were perforin−/−. However, mCP-CML, but not mBC-CML, relied on expression of programmed death-1 ligands 1 and 2 (PD-L1/L2) to resist T cell killing, because only GVL against mCP-CML was augmented when leukemias lacked PD-L1/L2. Thus, mBC-CML cells have cell-intrinsic mechanisms, distinct from mCP-CML cells, which protect them from T cell killing. |
Databáze: | OpenAIRE |
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