Abstract: Objective：To investigate the characteristics and clinical significances of ABL kinase domain mutations in tyrosine kinase inhibitor (TKI) resistant Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). Methods：The clinical characteristics, prognosis, molecular genetic characteristics, and ABL kinase domain mutations of 99 patients with Ph+ALL were retrospectively analyzed. Results：Among the 99 Ph+ALL patients, TKI resistance was identified in 38 patients with median 8 months from treatment to resistant occurrence. The 5-year overall survival (OS) rate and relapse free survival (RFS) rate in TKI resistant group was lower than those in non-resistant group (［34.2±8.0］% vs ［61.4±6.7］%, P=0.044; ［6.7±4.5］% vs ［68.6±6.8］%, P=0.000). A total of 32 patients developed TKI resistance during consolidation, and 13 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients treated with allo-HSCT had better 1-year OS rate compared with patients without allo-HSCT (［68.4±13.1］% vs ［17.8±9.2］%，P<0.001), while patients in two groups had similar 1-year PFS. Twelve kinds of mutations were detected in 10 amino acid sites, and 52.63% patients (20/38) had ABL kinase domain mutations. The most frequent mutation was T315I (45%), followed by E255K/V (40%) and Y253H/F (15%). Conclusions：The primary mechanism of TKI resistant in Ph+ALL patients was ABL kinase domain mutations, and T315I mutation was the most frequent. For patients with ABL kinase domain mutations, allo-HSCT is still an ideal treatment option.