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

Abstract

I mmunotherapeutic 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 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 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.

High expression of TARP correlates with inferior FLT3 mutations in non-adolescents and young adults with acute myeloid leukaemia

“…Consistent with a previous report [19], we observed significant overexpression of TARP mRNA in AML, especially in APL. The findings indicated that TARP might be correlated with APL pathogenesis; however, no significance in survival was observed in APL patients.…”

“…The core-binding factor (CBF) is a heterodimeric DNA-binding transcriptional regulator; CBF-AML comprises approximately 15% of cases of de novo adult AMLs and is considered a superior prognosis subgroup [21]. It was reported that high TARP expression was not restricted to FLT3-ITD in adult AML [19], we observed that aberrant TARP expression was significantly related to FLT3 alteration in non-AYA AML but not in AYA AML on the basis of bioinformatics analysis. Our data revealed the same trend, but no statistical significance was observed (Figure 2(G), p = .066), possibly due to the small sample size.…”

“…Recently, Barbara et al reported an aberrant higher expression of TARP in AML-LSCs than in normal haematopoietic stem cells (HSCs). As a leukaemic marker, TARP is an immunotherapeutic target in response to TARP-T-cell receptorengineered cytotoxic T cells [19]. Promotion of proliferation of cancerous cells induced by TARP was first observed in prostate cancer [20].…”

“…High TARP expression was associated with FLT3-ITD mutation and central nervous system involvement in paediatric AML patients but not in adult AML patients. In addition, TARP-T cell receptor-engineered cytotoxic T cells exhibited potent leukaemic cell-killing activities in vitro [19]. Unfortunately, no large studies A-F).…”

TARP as antigen in cancer immunotherapy

“…Essand et al illustrated that, the identified TCR γ transcript originates from prostate epithelial cells and not from infiltrating γδ T-lymphocytes or other prostatic cell types [ 17 ]. Although expression in healthy tissue is limited to the prostate, TARP is highly expressed in various cancers including androgen-sensitive prostate cancer [ 17 , 18 ], breast [ 18 ] and endometrial cancers [ 19 ], salivary gland tumors [ 20 ], and acute myeloid leukemia (AML) [ 21 , 22 ]. Upregulated TARP expression promotes tumor progression and metastasis [ 23 ], and correlates with unfavorable tumor characteristics [ 21 ].…”