{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:40:01Z","timestamp":1788878401180,"version":"build-2803163510"},"reference-count":36,"publisher":"American Society of Hematology","issue":"2","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>The internal tandem duplications in FMS-like tyrosine kinase 3 (FLT3-ITD) are associated with poor prognosis in acute myeloid leukemia (AML), yet its kinase-independent mechanisms remain unclear. To investigate kinase-independent immunosuppressive mechanisms in FLT3-ITD AML, we integrated single-cell RNA sequencing from 2 data sets and multiparameter flow cytometry data from 104 primary patient samples and identified CD8+ T-cell exhaustion as a hallmark of the FLT3-ITD immune microenvironment. Mechanistically, FLT3-ITD acts as a mutation-specific scaffold that assembles a ternary complex with protein kinase C iota (PKC\u03b9) and STAT1, as demonstrated by coimmunoprecipitation and colocalization. This complex enables PKC\u03b9-mediated phosphorylation of STAT1, at serine 727 (S727), thereby driving CD276 transcription independent of the canonical tyrosine 701 (Y701) site. Chromatin immunoprecipitation, electrophoretic mobility shift assays, promoter-reporter assays, and phosphosite-mutant constructs confirmed that S727 phosphorylation is necessary and sufficient for CD276 transactivation. Multiplex immunohistochemistry of bone marrow validated coelevation of pS727-STAT1 and CD276 in FLT3-ITD blasts, accompanied by CD8+ T-cell depletion. Functionally, CD276 upregulation induced profound CD8+ T-cell exhaustion, characterized by reduced cytotoxicity, impaired proliferation, diminished interferon-\u03b3 (IFN-\u03b3) production, and elevated inhibitory checkpoint expression. Targeting CD276 restored CD8+ T-cell function by 1.2- to 1.7-fold (cytotoxicity), 1.4- to 1.7-fold (proliferation), 1.5- to 1.8-fold (IFN-\u03b3 secretion), and 25.4% to 67.6% (checkpoint expression) in ex vivo coculture. In patient\u2013derived xenograft models, cotreatment with an FLT3 inhibitor (quizartinib) and CD276-targeting agents led to 72.9% to 80.4% tumor burden reduction and enhanced CD8+ T-cell function, outperforming quizartinib monotherapy. These findings define a scaffolded PKC\u03b9-pS727-STAT1 signaling axis that promotes immune evasion in FLT3-ITD AML, supporting combined FLT3, and CD276 targeting as a promising translational strategy in this aggressive leukemia subtype.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032254","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:47:12Z","timestamp":1774428432000},"page":"213-228","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":4,"title":["FLT3-ITD scaffolds PKC\u03b9-STAT1 to drive noncanonical S727 phosphorylation and CD276-driven CD8+ T-cell exhaustion in AML"],"prefix":"10.1182","volume":"148","author":[{"given":"Yun","family":"Wang","sequence":"first","affiliation":[{"name":"1Department of Hematological Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Centre for Cancer, Sun Yat-sen University Cancer 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