TARP is an immunotherapeutic target in acute myeloid leukemia expressed in the leukemic stem cell compartment

Barbara Depreter, Karin E Weening, Karl Vandepoele, Magnus Essand, Barbara De Moerloose, Maria Themeli, Jacqueline Cloos, Diana Hanekamp, Ine Moors, Inge D' Hont, Barbara Denys, Anne Uyttebroeck, An Van Damme, Laurence Dedeken, Sylvia Snauwaert, Glenn Goetgeluk, Stijn De Munter, Tessa Kerre, Bart Vandekerckhove, Tim LammensJan Philippé

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Immunotherapeutic strategies targeting the rare leukemic stem cell compartment 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 ã 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 compared to hematopoietic stem cells and normal myeloblasts (15 healthy controls). Moreover, TARP expression was significantly associated with a fmslike 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 expression 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.

Original languageEnglish
Pages (from-to)1306-1316
Number of pages11
JournalHaematologica
Volume105
Issue number5
Early online date1 Aug 2019
DOIs
Publication statusPublished - 1 May 2020

Cite this