Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Med. 2024 Oct;13(20):e70317. doi: 10.1002/cam4.70317.
Since the development of the first-generation Tyrosine Kinase Inhibitor (TKI), it has played a crucial role in the treatment of BCR::ABL1-positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). However, ABL1 kinase domain (ABL1 KD) mutations confer resistance to several TKIs. These mutations have been extensively studied in chronic myeloid leukemia (CML) but less so in BCR::ABL1-positive acute lymphoblastic leukemia (ALL).
Our study aimed to analyze the the ABL1 KD mutations in 97 consecutive newly-diagnosed adults with BCR::ABL1-positive ALL before therapy, in cytogenetic complete remission and at relapse with next generation sequencing (NGS). The relationship between ABL1 KD mutations and TKI selection was also analyzed.
Previously unreported ABL1 KD mutations R239G, F401V/L, R516L and K262T were the most prevalent in pre-therapy and cytogenetic remission samples, whereas T315I/P and P-loop mutations were most prevalent in relapse samples. R239G, F401V/L, R516L and K262T are related to the BCR::ABL1 structure, whereas T315I/P and P-loop mutations directly alter kinase activity. BaF3 cells transfected with ABL1 KD F401V, K262T, R239G, or R516L mutations were resistant to imatinib but strongly inhibited by olverembatinib with IC50 values of 0.73 to 1.52nM. Meanwhile, olverembatinib had advantages in increasing complete molecular response (CMR) and good prognosis.
Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.
自第一代酪氨酸激酶抑制剂（TKI）问世以来，它在治疗 BCR::ABL1 阳性急性淋巴细胞白血病（ALL）和慢性髓性白血病（CML）方面发挥了至关重要的作用。然而，ABL1 激酶结构域（ABL1 KD）突变导致对几种 TKI 的耐药性。这些突变在慢性髓性白血病（CML）中得到了广泛研究，但在 BCR::ABL1 阳性急性淋巴细胞白血病（ALL）中研究较少。
我们的研究旨在分析 97 例新诊断的成人 BCR::ABL1 阳性 ALL 患者在治疗前、细胞遗传学完全缓解和复发时的 ABL1 KD 突变，使用下一代测序（NGS）。还分析了 ABL1 KD 突变与 TKI 选择之间的关系。
在治疗前和细胞遗传学缓解样本中，以前未报道过的 ABL1 KD 突变 R239G、F401V/L、R516L 和 K262T 最为常见，而在复发样本中，T315I/P 和 P 环突变最为常见。R239G、F401V/L、R516L 和 K262T 与 BCR::ABL1 结构有关，而 T315I/P 和 P 环突变直接改变激酶活性。转染 ABL1 KD F401V、K262T、R239G 或 R516L 突变的 BaF3 细胞对伊马替尼耐药，但对奥瑞巴替尼的抑制作用很强，IC50 值为 0.73 至 1.52nM。同时，奥瑞巴替尼在提高完全分子缓解（CMR）和预后方面具有优势。
总的来说，我们的研究结果表明，新的 ABL1 KD 突变在 BCR::ABL1 阳性 ALL 患者中普遍存在且具有重要影响，这突出了针对这些突变的有效治疗方法的必要性。
