PF204 TARP AS IMMUNOTHERAPEUTIC TARGET IN AML EXPRESSED IN THE LSC COMPARTMENT
Bibliographic record
Abstract
Background: Acute myeloid leukemia (AML) accounts for 80% of adult and 20% of pediatric leukemias. Despite frequent initial remission, patients exhibit a high relapse risk, probably due to therapy‐resistant leukemic stem cells (LSCs). Particularly the prognosis of FLT3‐ITD harboring patients remains extremely poor. Aims: To identify LSC‐specific targets and develop immunotherapeutic strategies for LSC elimination while assuring salvage of normal hematopoietic stem cells (HSCs). Methods: The GSE 17054 micro‐array dataset was used for transcriptome analysis of CD34+CD38‐ populations sorted from de novo adult AML (LSCs, n = 9) and healthy adults (HSCs, n = 4). We next evaluated transcript expression in CD34+CD38‐ and CD34+CD38+ populations sorted from de novo pediatric AML (pedAML) and healthy controls. An 8x60K human gene expression micro‐array was performed in four pediatric AML (pedAML) (2 FLT3 WT, 2 FLT3‐ITD) and 3 cord blood samples. In addition, qPCR was performed in 13 pedAML, 17 adult AML, and 15 controls (cord blood, normal bone marrow and mobilized blood stem cells). Finally, cell lines of various origin, including 9 AML cell lines, were examined. Protein expression was evaluated by Western blotting and confocal microscopy. Viral transduction was used to generate T‐cell receptor (TCR)‐engineered cytotoxic T‐cells (CTLs), next to HLA‐A ∗ 0201 expressing, TARP overexpression and TARP knockdown AML cell lines. Killing by TCR‐engineered CTLs was evaluated in vitro by cytokine assays, flow cytometry‐ and bioluminescence‐based killing assays. Results: Re‐analysis of the GSE 17054 dataset revealed that the TCRγ chain alternate reading frame protein (TARP) was the most differentially expressed gene between LSC and HSC. Until now, TARP is known as a prostate‐specific marker, also expressed in breast adenocarcinoma. Subsequently, micro‐array and qPCR analysis showed aberrantly high TARP expression within pedAML and adult AML leukemic blasts and LSCs, while absent in normal counterparts. Noteworthy, all FLT3‐ITD harboring pedAML patients (n = 8) showed high TARP expression (P < 0.01), whereas this association was not significant for FLT3‐ITD adult AML (n = 9). No TARP transcripts were identified in B‐ALL, CML nor B‐cell lines, while expression in AML cell lines was significantly higher (P < 0.001). Aberrant TARP expression in cell lines and primary patient samples was confirmed at the protein level and confocal microscopy further corroborated these data. Importantly, cell lines and primary patient samples co‐expressing TARP and HLA‐A ∗ 0201 were efficiently killed by TARP‐TCR engineered CTLs, providing proof‐of‐concept that TARP qualifies as a physiologically relevant target for T‐cell therapy in AML. Summary/Conclusion: We showed that TARP is highly expressed in AML leukemic cells, including LSCs, while absent in normal counterparts. High TARP expression is significantly associated with FLT3‐ITD in pedAML, a marker for poor prognosis. TARP‐TCR engineered CTLs effectively killed TARP+ HLA‐A ∗ 0201+ co‐expressing AML cell lines and primary leukemic cells in vitro . To the best of our knowledge, this is the first report indicating that TARP‐TCR engineered CTLs hold great promise for immunotherapeutic T‐cell therapy in AML.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.031 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".