Page 146 - Haematologica May 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1306-1316
Acute Lymphoblastic Leukemia
TARP is an immunotherapeutic target in acute myeloid leukemia expressed in the leukemic stem cell compartment
Barbara Depreter,1,2 Karin E. Weening,2,3 Karl Vandepoele,2,4 Magnus Essand,5 Barbara De Moerloose,1,2,6 Maria Themeli,7 Jacqueline Cloos,7
Diana Hanekamp,7 Ine Moors,8 Inge D’hont,6 Barbara Denys,2,4
Anne Uyttebroeck,9 An Van Damme,10 Laurence Dedeken,11
Sylvia Snauwaert,12 Glenn Goetgeluk,3 Stijn De Munter,2,3 Tessa Kerre,2,8 Bart Vandekerckhove,2,3 Tim Lammens1,2* and Jan Philippé2,3,4*
1Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; 2Cancer Research Institute Ghent, Ghent University, Ghent, Belgium; 3Department of Diagnostic Sciences, Ghent University, Ghent, Belgium; 4Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium; 5Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; 6Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium; 7Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands; 8Department of Hematology, Ghent University Hospital, Ghent, Belgium; 9Department of Pediatrics, University Hospital Gasthuisberg, Louvain, Belgium; 10Department of Pediatric Hematology Oncology, University Hospital Saint-Luc, Brussels, Belgium; 11Department of Pediatric Hematology Oncology, Queen Fabiola Children's University Hospital, Brussels, Belgium and 12Department of Hematology, AZ Sint-Jan Hospital Bruges, Bruges, Belgium
ABSTRACT
Immunotherapeutic strategies targeting the rare leukemic stem cell com- partment might provide salvage to the high relapse rates currently observed in acute myeloid leukemia (AML). We applied gene expression profiling for comparison of leukemic blasts and leukemic stem cells with their normal counterparts. Here, we show that the T-cell receptor γ chain alternate reading frame protein (TARP) is over-expressed in de novo pediatric (n=13) and adult (n=17) AML sorted leukemic stem cells and blasts com- pared to hematopoietic stem cells and normal myeloblasts (15 healthy con- trols). Moreover, TARP expression was significantly associated with a fms- like tyrosine kinase receptor-3 internal tandem duplication in pediatric AML. TARP overexpression was confirmed in AML cell lines (n=9), and was found to be absent in B-cell acute lymphocytic leukemia (n=5) and chronic myeloid leukemia (n=1). Sequencing revealed that both a classical TARP transcript, as described in breast and prostate adenocarcinoma, and an AML-specific alternative TARP transcript, were present. Protein expres- sion levels mostly matched transcript levels. TARP was shown to reside in the cytoplasmic compartment and showed sporadic endoplasmic reticulum co-localization. TARP-T-cell receptor engineered cytotoxic T-cells in vitro killed AML cell lines and patient leukemic cells co-expressing TARP and HLA-A*0201. In conclusion, TARP qualifies as a relevant target for immunotherapeutic T-cell therapy in AML.
Introduction
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy, accounting for 80% of adult1-4 and 20% of pediatric5-7 leukemia. Despite initial clin- ical remission rates of 60-90%,2,5,6 patients exhibit a high relapse risk and therapy- related mortality, resulting in a 5-year overall survival of 30% in adult AML1,3 and 65-70% in pediatric AML (pedAML).5,8 Especially the prognosis of patients with fms-like tyrosine kinase receptor-3 internal tandem duplications (FLT3-ITD) remains extremely poor.2,8,9 The high relapse rate is thought to arise from a chemotherapy-resistant cell fraction with unlimited self-renewal capacities,
*JP and TL contributed equally to this work as co-senior authors.
Correspondence:
TIM LAMMENS
tim.lammens@ugent.be
Received: March 21, 2019. Accepted: July 12, 2019. Pre-published: August 1, 2019.
doi:10.3324/haematol.2019.222612
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