Overexpression of TREM1 predicts poor prognosis and chemotherapy resistance in Egyptian acute myeloid leukemia associated with FLT3 internal tandem duplication and CD123 expression and stemness signatures

Abstract

BACKGROUND: Despite advances, over half of AML patients relapse or become refractory to chemotherapy. TREM1 (CD354), a regulator of tumor inflammation and immune evasion in solid cancers, remains poorly characterized in AML, especially in underrepresented populations like Egyptians. We aimed to evaluate TREM1 expression in de novo AML, its association with high-risk features (FLT3-ITD, CD123), and its prognostic impact on treatment response and survival. METHODS: In this prospective case-control study, TREM1 expression was quantified via flow cytometry (APC-conjugated anti-CD354) in 50 newly diagnosed AML patients and 50 matched controls. Patients were risk-stratified per ELN 2022 guidelines and treated with standard induction chemotherapy. TREM1 levels (CD45dim/SSC-low blasts) were correlated with molecular markers (FLT3-ITD, NPM1, cytogenetics), immunophenotypic profiles (CD2/CD7/CD19/CD56/CD123), and clinical outcomes (remission, survival). Statistical analyses included ROC-derived thresholds, Kaplan-Meier survival, and multivariate regression (SPSS v20.0). RESULTS: Key findings revealed significant TREM1 overexpression in AML blasts (median 21% [IQR: 12.8-43%]) compared to controls (15% [13-18%]; p = 0.01). Elevated TREM1 expression (> 21%) robustly predicted adverse prognosis (70% sensitivity, 75% specificity; AUC = 0.70, p = 0.04), chemotherapy resistance (non-complete remission: 77.8% sensitivity, 87% specificity; AUC = 0.80, p < 0.001), and inferior overall survival (median 5.5 vs. 11 months for low TREM1; p = 0.02). Notably, TREM1 expression correlated strongly with FLT3-ITD mutations (45.9% vs. 12.1% in wild-type; p = 0.01) and CD123 positivity (r = 0.29, p = 0.03), and was enriched in MLL-rearranged and complex karyotype subgroups (p = 0.04). Time-dependent ROC analysis confirmed sustained predictive accuracy (6-month AUC = 0.81), while TREM1/FLT3-ITD co-expression conferred a 5.4-fold mortality risk (p = 0.008). Subgroup analyses revealed consistent prognostic value across ELN risk categories. CONCLUSIONS: These results establish TREM1 as a biomarker of high-risk AML characterized by FLT3/CD123 co-expression, intrinsic chemotherapy resistance, and poor survival. The prognostic utility of TREM1 (cutoff > 21%) may enhance risk stratification, while its immunomodulatory function underscores its potential as a therapeutic target. Future studies should validate these findings in larger, multiethnic cohorts and explore the mechanistic links between TREM1 and AML pathogenesis.