Chanswangphuwana Chantiya, Sukswai Narittee, Tangnuntachai Nichthida, Rojnuckarin Ponlapat
Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Rama IV Road, Patumwan, Bangkok, 10330, Thailand.
Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
Ann Hematol. 2024 Dec;103(12):5417-5423. doi: 10.1007/s00277-024-06124-w. Epub 2024 Dec 4.
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 NPM1FLT3-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 NPM1FLT3-ITD AML. Further studies with the large number of patients are warranted.
核磷蛋白1（NPM1）突变的急性髓系白血病（AML）且无FLT3-ITD突变被归类为低危AML，对阿糖胞苷治疗反应良好。缺氧诱导因子-1α（HIF-1α）促进白血病细胞存活并维持白血病干细胞静止，可能导致阿糖胞苷耐药。本研究采用免疫组织化学方法评估了29例新诊断的NPM1 FLT3-ITD正常核型AML患者骨髓中HIF-1α的表达，并分析其与生存的相关性。所有患者在标准诱导化疗后均达到完全缓解，并进行阿糖胞苷巩固治疗。分别在34.5%和58.6%的患者中发现了呈高尔基体模式的HIF-1α阳性染色和强细胞质HIF-1α表达。高尔基体或强细胞质HIF-1α表达与复发增加相关（p = 0.048），无复发生存期（RFS）显著较差（p = 0.042）。多因素分析显示，诊断时的髓外疾病是不良RFS的独立预后因素（风险比[HR] 3.82；95%置信区间[CI] 1.26 - 11.55，p = 0.018），而高尔基体或强细胞质HIF-1α表达显示出RFS不良的趋势（HR 3.56；95% CI 1.00 - 12.69，p = 0.050）。总之，高HIF-1α表达可能是NPM1 FLT3-ITD AML中RFS不良和阿糖胞苷耐药的基线预后生物标志物。有必要对大量患者进行进一步研究。
