Survival impact of hypoxia-inducible factor-1 alpha (HIF-1α) in Nucleophosmin1 mutated acute myeloid leukemia

Nucleophosmin1 (NPM1) mutated acute myeloid leukemia (AML) without FLT3-ITD mutation is classified as a favorable risk AML which responds well to cytarabine therapy. Hypoxia-inducible factor-1 alpha (HIF-1α) promotes leukemic cell survival and maintains leukemic stem cell quiescence possibly contributing to cytarabine resistance. This study evaluated HIF-1α expression using immunohistochemistry in bone marrow of 29 newly diagnosed NPM1⁺FLT3-ITD⁻ normal karyotype AML patients and analyzed its correlation with survival. All patients achieved complete remission after standard induction chemotherapy and proceeded to cytarabine consolidations. Positive HIF-1α staining with golgi body pattern and strong cytoplasmic HIF-1α expression was identified in 34.5% and 58.6% of patients, respectively. The expression of golgi body or strong cytoplasmic HIF-1α expression was related to increased relapse (p = 0.048) with significantly inferior relapse-free survival (RFS, p = 0.042). Using multivariate analysis, extramedullary disease at diagnosis was revealed as an independent prognostic factor for adverse RFS (hazard ratio [HR] 3.82; 95% confidence interval [CI] 1.26–11.55, p = 0.018), while golgi body or strong cytoplasmic HIF-1α expression showed a trend toward poor RFS (HR 3.56; 95% CI 1.00–12.69, p = 0.050). In summary, high HIF-1α expression is potentially a baseline prognostic biomarker for poor RFS and cytarabine resistance in NPM1⁺FLT3-ITD⁻ AML. Further studies with the large number of patients are warranted.