{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:36Z","timestamp":1792790436883,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Cancer Biology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/00v7th354","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Edward P. 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We performed high dimensional immune profiling of bone marrow samples from 46 newly diagnosed AML patients using mass cytometry to probe the microenvironment and T cell states. We used single-cell RNA and T cell receptor (TCR) sequencing to define CD8 T cell phenotypes, transcriptional states, and clonal architecture. AML-associated CD8 T cells were skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), while canonically exhausted T cell populations were rare. Functional studies revealed that TEMRA CD8 T cells robustly produced IFN\u03b3 and TNF\u03b1 upon in vitro stimulation. Clonal expansion was concentrated within the TEMRA compartment. Comparison of TCR sequences with known viral epitopes identified a small subset of expanded viral-specific clonotypes, while the majority of highly expanded clonotypes had unknown specificity and may include AML-specific T cells. Differential gene expression analysis revealed shared cytotoxic effector programs during clonal expansion but diverging activation signatures: viral-specific clones upregulated canonical T cell receptor signaling genes, whereas expanded clones of unknown specificity exhibited enrichment of natural killer (NK) receptor-associated genes. These genes comprised the leukemia-associated NK-immune (LaNKi) score which was elevated in an independent AML dataset compared to pan cancer tumor infiltrating lymphocytes. These findings define the CD8 T cell differentiation landscape and clonal architecture in AML marrow at diagnosis and suggest that T cell dysfunction in AML diverges from classical activation and exhaustion paradigms.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>CD8 T cells in AML are enriched for terminally differentiated states not defined by traditional checkpoint-inhibitor expression.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The LaNKi score marks clonally expanded CD8 T cells of unknown specificity and is validated across independent AML and pan-cancer datasets.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.30.755147","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:20:19Z","timestamp":1790932819000},"source":"Crossref","is-referenced-by-count":0,"title":["Clonally Expanded CD8 T Cells in AML Adopt an NK-Like Program Distinct from Canonical Exhaustion"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6120-1496","authenticated-orcid":false,"given":"Yunli E","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0619-1605","authenticated-orcid":false,"given":"Matthew A","family":"Cottam","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-2474","authenticated-orcid":false,"given":"Chad R","family":"Potts","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8449-0139","authenticated-orcid":false,"given":"Thomas","family":"Gracie","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciarra","family":"Polsley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4150-5070","authenticated-orcid":false,"given":"Justin A","family":"Cartailler","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program, Northwestern University, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3763-5504","authenticated-orcid":false,"given":"Michael R","family":"Savona","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1593-2612","authenticated-orcid":false,"given":"Rui","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7110-2416","authenticated-orcid":false,"given":"Stanley C","family":"Lee","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-9469","authenticated-orcid":false,"given":"Robert","family":"Welner","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1140-9154","authenticated-orcid":false,"suffix":"Jr","given":"P Brent","family":"Ferrell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100710100931000_2026.09.30.755147v1.1","unstructured":"Acute Myeloid Leukemia -Cancer Stat Facts. 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