Loscocco Federica, Visani Giuseppe, Ruzzo Annamaria, Bagaloni Irene, Fuligni Fabio, Galimberti Sara, Di Paolo Antonello, Stagno Fabio, Pregno Patrizia, Annunziata Mario, Gozzini Antonella, Barulli Sara, Gabucci Elisa, Magnani Mauro, Isidori Alessandro
Hematology and Hematopoietic Stem Cell Transplant Center, AORMN, Pesaro, Italy.
Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Fano, Italy.
Front Oncol. 2021 May 13;11:672287. doi: 10.3389/fonc.2021.672287. eCollection 2021.
Tyrosine kinase inhibitors (TKIs) have radically changed the outcome of chronic myeloid leukemia (CML) patients in the last 20 years. Moreover, the advent of second generation TKIs, namely nilotinib and dasatinib, have largely increased the number of CML patients achieving deep and sustained molecular responses. However, the possible mechanisms capable of influencing the maintenance of the long-term molecular response are not yet fully known and understood. In this light, polymorphisms in MDR-ABC transporters may influence the efficacy and safety of TKIs. In this study, we examined seven single nucleotide polymorphisms (SNPs) in four ABC transporter genes: ABCC1 rs212090 (5463T>A), ABCC2 rs3740066 (3972C>T), ABCC2 rs4148386 G>A, ABCC2 rs1885301 (1549G>A), ABCG2 rs2231137 (34G>A), ABCG2 rs2231142 G>C, ABCB1 rs1045642 (3435C>T), to determine their effect on the achievement and/or loss of molecular response in 90 CML patients treated with nilotinib. We found that rs3740066 CC and CT as well as the rs1045642 TT genotypes correlated with a higher probability to achieve MR3 in a shorter time (=0.02, =0.004, and =0.01), whereas rs2231137 GG was associated with lower probability of MR3 achievement (=0.005). Moreover, rs3740066 CC genotype, the rs1045642 CC and TT genotypes were positively correlated with MR4 achievement (=0.02, =0.007, and =0.003). We then generated a predictive model incorporating the information of four genotypes, to evaluate the combined effect of the SNPs. The combination of SNPs present in the model affected the probability and the time to molecular response. This model had a high prognostic significance for both MR3 and MR4 (=0.005 and =0.008, respectively). Finally, we found rs2231142 GG genotype to be associated with a decrease risk of MR3 loss. In conclusion, MDR-transporters SNPs may significantly affect the achievement and loss of molecular response in CML patients treated with nilotinib.
在过去20年中，酪氨酸激酶抑制剂（TKIs）彻底改变了慢性髓性白血病（CML）患者的治疗结局。此外，第二代TKIs即尼洛替尼和达沙替尼的出现，极大地增加了实现深度和持续分子反应的CML患者数量。然而，能够影响长期分子反应维持的可能机制尚未完全知晓和理解。鉴于此，多药耐药ABC转运蛋白的多态性可能会影响TKIs的疗效和安全性。在本研究中，我们检测了四个ABC转运蛋白基因中的七个单核苷酸多态性（SNP）：ABCC1 rs212090（5463T>A）、ABCC2 rs3740066（3972C>T）、ABCC2 rs4148386 G>A、ABCC2 rs1885301（1549G>A）、ABCG2 rs2231137（34G>A）、ABCG2 rs2231142 G>C、ABCB1 rs1045642（3435C>T），以确定它们对90例接受尼洛替尼治疗的CML患者分子反应的获得和/或丧失的影响。我们发现rs3740066 CC和CT以及rs1045642 TT基因型与在更短时间内实现MR3的更高概率相关（分别为=0.02、=0.004和=0.01），而rs2231137 GG与实现MR3的较低概率相关（=0.005）。此外，rs3740066 CC基因型、rs1045642 CC和TT基因型与MR4的实现呈正相关（分别为=0.02、=0.007和=……此处原文有误应为=0.003）。然后，我们生成了一个纳入四种基因型信息的预测模型，以评估SNP的联合效应。模型中存在的SNP组合影响了分子反应的概率和时间。该模型对MR3和MR4均具有较高的预后意义（分别为=0.005和=0.008）。最后，我们发现rs2231142 GG基因型与MR3丧失风险降低相关。总之，多药耐药转运蛋白SNP可能会显著影响接受尼洛替尼治疗的CML患者分子反应的获得和丧失。
