Genomes and Genes
Leukemia Stem Cells: Essential Targets for GVL and Mediators of GVL-Resistance
Principal Investigator: Warren D Shlomchik
Abstract: Much of the efficacy of allogeneic stem cell transplantation in treating hematologic malignancies is due to the T cell-mediated graft-vs-leukemia (GVL) effect. Chronic phase CML (CP-CML) is the most GVL-sensitive leukemia as demonstrated by a 5-fold increased risk of relapse in recipients of T cell-depleted grafts and a nearly 80% complete response rate in recipients of donor leukocyte infusions. Unfortunately, most other neoplasms are relatively GVL-resistant. The basis for differential susceptibility, even between such closely related leukemias as CP-CML and GVL-resistant blast crisis CML (BC-CML) is unknown. A detailed understanding of the mechanisms underlying GVL-resistance is the key first step in developing clinical approaches to make GVL-resistant cancers more GVL-sensitive. An obstacle in achieving this goal has been the absence of mouse models for GVL-sensitive and -resistant leukemias that share etiology and phenotype with their human counterparts. To address this we have been dissecting GVL responses against mouse models of GVL-sensitive chronic phase and GVL-resistant blast crisis CML. Mouse chronic phase CML (mCP-CML) is induced by the retroviral transduction of mouse bone marrow with bcr-abl. Mouse blast crisis CML (mBC-CML) is created by transducing bone marrow with both bcr-abl and a fusion between NUP98 and HOXA9 (NH). bcr-abl is the defining molecular abnormality in CML and NH is a "second hit" found in BC-CML. That leukemias are generated with retrovirus has allowed the creation of gene-deficient leukemias which are used to study GVL effector mechanisms. In sum, the basic mechanisms of T cell killing against mCP and mBC-CML are shared: cognate interactions between T cells and leukemias are required and impairment of any single effector mechanism does not diminish GVL. Nonetheless, in each case mBC-CML is relatively GVL-resistant. In order to better understand GVL-resistance, we have been working to identify the leukemia stem cells (LSC) for both mCP-CML and mBC-CML. The central hypothesis of this proposal is that LSCs are the key targets of GVL and that GVL resistance occurs in the interaction between effector T cells and the mBC-CML LSC. We will identify and purify mBC-CML and mCP-CML LSCs (Aim 1) and characterize them by flow cytometry and gene expression profiling to identify potential molecules that might promote GVL-resistance or sensitivity (Aim 2). We will develop novel in vitro and in vivo CTL assays against LSCs in Aim 3 using a method that allows a comparison of the sensitivity of mBC and mCP LSCs that express defined levels of the target peptide:MHCI complex. In Aim 4 we will create additional genetically-modified leukemias that underexpress or overexpress candidate mediators of GVL-resistance or -sensitivity (discovered in Aim 2). We will then test these leukemias in GVL experiments and their LSCs in the CTL assays developed in Aim 3. In this way we will have established a system for both identifying and validating candidate pathways for manipulation in clinical studies, which is our long-term objective. PUBLIC HEALTH RELEVANCE: Many people die from cancers of blood cells. Frequently immune cells, given as part of a bone marrow transplant from another person, are used to try to cure these patients. Unfortunately, for reasons that are unknown, many cancers are resistant to this therapy and this proposal will investigate the biology underlying this differential sensitivity.
Funding Period: 2002-09-01 - 2015-01-31
more information: NIH RePORT
- Graft-versus-host diseaseWarren D Shlomchik
Yale University School of Medicine, sections of Medical Oncology and Immunobiology, PO Box 208032, New Haven, Connecticut 06520, USA
Nat Rev Immunol 7:340-52. 2007..This Review focuses on research in mouse models pursued to achieve this goal...
- Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host diseaseHong Zheng
Penn State Milton S Hershey Medical Center, Department of Medicine, Hershey, PA, USA
Blood 111:2476-84. 2008....
- CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVLCatherine Matte-Martone
Section of Medical Oncology, Cancer Center, Yale University School of Medicine, New Haven, CT 06520 8032, USA
Blood 111:3884-92. 2008..Thus, CD4 cells use distinct effector mechanisms in GVHD and GVL: direct cytolytic action is required for GVL but not for GVHD. If these noncytolytic pathways can be inhibited, then GVHD might be ameliorated while preserving GVL...
- Central memory CD8+ T cells induce graft-versus-host disease and mediate graft-versus-leukemiaHong Zheng
Department of Medicine, Penn State Milton S Hershey Medical Center, Hershey, PA 17033, USA
J Immunol 182:5938-48. 2009..Thus, in contrast to what was previously thought, CD8(+) T(CM) are capable of inducing GVHD and are substantially different from T(EM) but only subtly so from T(N)...
- Recipient B cells are not required for graft-versus-host disease inductionCatherine Matte-Martone
Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06620, USA
Biol Blood Marrow Transplant 16:1222-30. 2010..These data indicate that recipient B cells are not important initiators of GVHD, and that efforts to prevent GVHD by APC depletion should focus on other APC subsets...
- 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 resistCatherine Matte-Martone
Department of Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA
J Immunol 187:1653-63. 2011..Thus, mBC-CML cells have cell-intrinsic mechanisms, distinct from mCP-CML cells, which protect them from T cell killing...
- Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitutionNing Li
Department of Medicine, Yale University School of Medicine Cancer Center, New Haven, CT 06520 8032, USA
Blood 118:5965-76. 2011..These data establish a strategy for augmenting GVL and immune reconstitution without elaborate T-cell manipulation...