Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
Discipline of Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
Leuk Lymphoma. 2021 May;62(5):1157-1166. doi: 10.1080/10428194.2020.1861275. Epub 2021 Jan 2.
Acute lymphoblastic leukemia remains a leading cause of cancer-related death in children. Furthermore, subtypes such as Ph-like ALL remain at high-risk of relapse, and treatment resistance remains a significant clinical issue. The patient-derived Ph-like ALL fusion gene was transduced into Ba/F3 cells and allowed to become resistant to the tyrosine kinase inhibitors (TKIs) imatinib or dasatinib, followed by secondary resistance to ponatinib. Ba/F3 cells developed the clinically relevant p.T315I mutation and upon secondary resistance to ponatinib, developed compound mutations, including a novel p.L302H mutation. Significantly, compound mutations were targetable with a combination of asciminib and ponatinib. modeling of Ph-like ALL has identified kinase domain mutations in response to TKI treatment, that may have important clinical ramifications. Early detection of mutations is paramount to guide treatment strategies and improve survival in this high-risk group of patients.
急性淋巴细胞白血病仍然是导致儿童癌症相关死亡的主要原因。此外，Ph 样急性淋巴细胞白血病等亚型仍然存在高复发风险，治疗耐药仍然是一个重大的临床问题。该患者来源的 Ph 样急性淋巴细胞白血病融合基因被转导到 Ba/F3 细胞中，并使其对酪氨酸激酶抑制剂（TKI）伊马替尼或达沙替尼产生耐药性，随后对 ponatinib 产生继发性耐药性。Ba/F3 细胞发生了临床相关的 p.T315I 突变，在 ponatinib 产生继发性耐药性后，发生了复合突变，包括一种新的 p.L302H 突变。重要的是，asciminib 和 ponatinib 的联合用药可以靶向这些复合突变。Ph 样急性淋巴细胞白血病的建模已经确定了对 TKI 治疗的激酶结构域突变，这可能具有重要的临床意义。早期检测突变对于指导治疗策略和改善这一高危患者群体的生存至关重要。
