An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia

Zicong Huang; Ling Zhang; Xiaoyuan Gong; Jia Li; Shiyu Deng; Zihong Cai; Bingqing Tang; Kangyu Huang; Xin Li; Weihua Zhao; Yang Xu; Li Xuan; Qifa Liu; Ying Wang; Suning Chen; Hongsheng Zhou

doi:10.1002/hem3.82

An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia

Hemasphere. 2024 May 21;8(5):e82. doi: 10.1002/hem3.82. eCollection 2024 May.

Authors

Zicong Huang^{1

2

3}, Ling Zhang⁴, Xiaoyuan Gong⁵, Jia Li^{1

2}, Shiyu Deng^{1

2}, Zihong Cai^{1

2}, Bingqing Tang^{1

2}, Kangyu Huang^{1

2}, Xin Li⁶, Weihua Zhao⁷, Yang Xu⁴, Li Xuan^{1

2}, Qifa Liu^{1

2}, Ying Wang⁵, Suning Chen⁴, Hongsheng Zhou^{1

2

3}

Affiliations

¹ Department of Hematology, Nanfang Hospital Southern Medical University Guangzhou China.
² Guangdong Provincial Clinical Research Center for Hematologic Diseases, Nanfang Hospital Southern Medical University Guangzhou China.
³ Department of Hematology Ganzhou People's Hospital (Nanfang Hospital Ganzhou Hospital) Ganzhou China.
⁴ National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology The First Affiliated Hospital of Soochow University Suzhou China.
⁵ State Key Laboratory of Experimental Hematology Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College Tianjin China.
⁶ Department of Hematology, The Third Xiangya Hospital Central South University Changsha China.
⁷ Department of Hematology The First Affiliated Hospital of Guangxi Medical University Nanning China.

Abstract

Philadelphia 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.