HOX-PBX Up-regulation Predicts Favorable Prognosis in NPM1-mutated Normal Cytogenetic AML via WNT Signaling

Background/Aim: Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy. HOX gene dysregulation, particularly within the HOXA cluster, plays a critical role in leukemogenesis. This study investigated the impact of HOX-PBX gene expression and its association with clinical outcomes in NPM1-mutated cytogenetically normal (CN)-AML.

Materials and Methods: Gene expression analysis was performed on diagnostic bone marrow samples from 35 CN-AML patients using the NanoString nCounter platform. Differential expression of HOXA9, HOXA10, and PBX3 was assessed, along with correlations with NPM1 mutation status and WNT pathway activation. Kaplan–Meier survival analysis was conducted to evaluate prognostic significance.

Results: HOXA9 and HOXA10 were significantly up-regulated in NPM1-mutated AML compared to NPM1-negative cases (p<0.001). PBX3 expression strongly correlated with HOXA10 (r=0.86, p<0.001), suggesting a cooperative role in leukemogenesis. Elevated HOXA9 (>589.7) was associated with improved survival (hazard ratio=0.3, p=0.021). Up-regulated WNT pathway targets (MYC, RUNX1) in NPM1-mutated cases indicate active WNT/β-catenin signaling, potentially promoting differentiation and favorable prognosis.

Conclusion: HOX-PBX-WNT interactions contribute to the distinct biology of NPM1-mutated CN-AML. Targeting this axis may offer novel therapeutic strategies for AML, warranting further research into molecular-driven treatments for AML.