Inhibition of inositol kinase B controls acute and chronic graft-versus-host disease

Author:

Thangavelu Govindarajan1,Du Jing1,Paz Katelyn G.1,Loschi Michael1,Zaiken Michael C.1ORCID,Flynn Ryan1,Taylor Patricia A.1,Kirchmeier Andrew Kemal1ORCID,Panoskaltsis-Mortari Angela1,Luznik Leo2,MacDonald Kelli P.3,Hill Geoffrey R.3,Maillard Ivan4,Munn David H.56,Serody Jonathan S.7ORCID,Murphy William J.89,Miklos David10ORCID,Cutler Corey S.11,Koreth John11,Antin Joseph H.11,Soiffer Robert J.11,Ritz Jerome11ORCID,Dahlberg Carol12,Miller Andrew T.12ORCID,Blazar Bruce R.1

Affiliation:

1. Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;

2. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD;

3. Department of Immunology, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute and School of Medicine, University of Queensland, Brisbane, QLD, Australia;

4. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;

5. Georgia Cancer Center and

6. Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA;

7. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC;

8. Department of Dermatology and

9. Department of Internal Medicine, Laboratory of Cancer Immunology, University of California Davis Medical Center, Sacramento, CA;

10. Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA;

11. Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and

12. The Genomics Institute, Novartis Research Foundation (GNF), San Diego, CA

Abstract

T-cell activation leads to regulated increases in cytoplasmic calcium through inositol 1,4,5-triphosphate (IP3), a process balanced by phosphorylation and inactivation of IP3 by inositol 1,4,5-trisphosphate 3-kinase B (Itpkb). The investigators demonstrate that inhibition of Itpkb sustains increased intracellular Ca, leads to T-cell apoptosis, and inhibits graft-versus-host disease without impairing graft-versus-leukemia effects.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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