An Integrated Classification of Tumor Suppressor IKZF1 Inactivation and Oncogenic Activation in Philadelphia Chromosome‐like Acute Lymphoblastic Leukemia

AbstractPhiladelphia chromosome (Ph)‐like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high‐risk subset of Ph‐like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1, resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph‐like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling (CRLF2/EPOR/JAK2 rearrangements or p‐CRKL/p‐STAT5 high expression) had the worst outcome (3‐year overall survival [OS] of 28.8% vs. 80.1% for others, p < 0.001; 2‐year event‐free survival [EFS] of 6.5% vs. 57.0% for others, p < 0.001). Multivariable analysis demonstrated that this high‐risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35–8.81, p < 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99–5.39, p < 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high‐risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph‐like ALL.