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

Abstract

GVL against chronic phase CML (CP-CML) is potent, but it is less efficacious against acute leukemias and blast crisis CML (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 and 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 as GVL was similar against wild type or mBC-CML genetically lacking Fas, TRAIL-R, Fas/TRAIL-R, TNFR1/R2 or when donor T cells were perforin−/−. However, mCP-CML but not mBC-CML, relied on expression of PD-ligands to resist T cell killing, as 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 that protect them from T cell killing.

Alloantigen presentation and graft-versus-host disease: fuel for the fire

“…Thus, the expression of MHC class I on target cells is required for CD8 1 T-cell-dependent GVHD and GVL, whereas MHC class II expression is required for CD4 1 T-celldependent GVL, but not GVHD. 94,95 The latter is due to the fact that inflammatory cytokines produced by CD4…”

Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

“…The NUP98-HOXA9 fusion is a second-hit translocation in BC-CML that has also been identified in de novo AML (14)(15)(16)(17)(18)(19)(20)(21)(22), as have NUP98 fusions with other class I HOX genes. mCP-CML and mBC-CML are therefore excellent phenocopies and genocopies of their human counterparts, have defined stem cell populations (15,23), and, importantly, are GVL sensitive and GVL resistant, respectively (11). A powerful advantage of this approach is that, by transducing BM from gene-deficient mice, we can create gene-deficient leukemias as a means to explore mechanisms of GVL resistance (10,11,(24)(25)(26).…”

“…To understand the mechanisms of GVL resistance, we used mouse models to evaluate GVL against CP-CML (mCP-CML) and BC-CML (mBC-CML) (9)(10)(11). mCP-CML is created via retroviral transfer of the BCR-ABL fusion cDNA, the defining genetic abnormality of CP-CML, into mouse BM cells (12,13), whereas mBC-CML is created via retroviral transfer of both BCR-ABL and nucleoporin 98-homeobox A9 (NUP98-HOXA9) fusion cDNAs (14,15).…”

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

“…The blast-crisis chronic myelogenous leukemia (BC-CML) model was generated previously 22,23 and was a gift from Shlomchik's laboratory. B10.D2 donor grafts were given to lethally irradiated BALB/c recipients with or without BC-CML cells at a dose of 1 3 10 6 BC-CML cells per mouse together with TCD-BM (5 3 10 6 per mouse) with or without whole splenocytes (5 3 10 6 per mouse).…”