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Type: Journal article
Title: Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes
Author: Jiao, Y.
Davis, J.E.
Rautela, J.
Carrington, E.M.
Ludford-Menting, M.J.
Goh, W.
Delconte, R.B.
Souza-Fonseca-Guimaraes, F.
Koldej, R.
Gray, D.
Huang, D.
Kile, B.T.
Lew, A.M.
Ritchie, D.S.
Huntington, N.D.
Citation: Cell Death and Differentiation, 2019; 26(8):1516-1530
Publisher: Nature Publishing Group
Issue Date: 2019
ISSN: 1350-9047
Statement of
Yuhao Jiao, Joanne E. Davis, Jai Rautela, Emma M. Carrington, Mandy J. Ludford-Menting ... Benjamin T. Kile ... et al.
Abstract: Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft-versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD.
Keywords: Killer Cells, Natural
Mice, Inbred BALB C
Mice, Inbred C57BL
Proto-Oncogene Proteins c-bcl-2
Antineoplastic Agents
Bone Marrow Transplantation
Transplantation, Homologous
Administration, Oral
Cell Differentiation
Structure-Activity Relationship
Dose-Response Relationship, Drug
HEK293 Cells
Bridged Bicyclo Compounds, Heterocyclic
Rights: © ADMC Associazione Differenziamento e Morte Cellulare 2018.
DOI: 10.1038/s41418-018-0228-y
Grant ID:
Appears in Collections:Aurora harvest 8
Molecular and Biomedical Science publications

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