Haematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, U13/52 Setia Alam, 40170, Shah Alam, Selangor, Malaysia.
Sector for Evidence Based Healthcare, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia.
BMC Cancer. 2022 Mar 26;22(1):332. doi: 10.1186/s12885-022-09396-5.
Tyrosine kinase inhibitors (TKIs) as first-line therapy for Chronic Myeloid Leukemia (CML) show a high success rate. However, a low number of patients with long-term treatment-free remission (TFR) were observed. Molecular relapse after imatinib discontinuation occurred at 50% at 24 months, with 80% occurrence within the first 6 months. One of the reasons for relapse is untimely TKIs discontinuation caused by large errors from estimates at very low-level or undetectable disease, thus warranting new biomarkers for CML.
Next Generation Sequencing (NGS) was used to identify microRNAs (miRNAs) at the molecular response in CML adult patients receiving TKIs treatment. A total of 86 samples were collected, 30 from CML patients responsive and 28 from non-responsive to imatinib therapy, and 28 from blood donors. NGS was conducted whereby 18 miRNAs were selected and validated by real-time RT-qPCR in triplicate.
Hsa-miR-181a-5p was expressed significantly (p-value< 0.05) with 2.14 and 2.33-fold down-regulation in both patient groups, respectively meanwhile hsa-miR-182-5p and hsa-miR-26a-5p were significant only in the non-responsive group with 2.08 and 2.39 fold up-regulation. The down-regulation was consistent with decreased amounts of BCR-ABL1 in patients taking TKIs regardless of molecular responses. The up-regulation was consistent with the substantial presence of BCR-ABL1 in CML patients treated with TKIs at the molecular response.
Therefore, these miRNAs have potential as new therapeutic biomarkers for BCR-ABL1 status in adult CML patients treated with TKIs at molecular responses. These could improve current approaches and require further analysis to look for targets of these miRNAs in CML.
酪氨酸激酶抑制剂（TKI）作为慢性髓性白血病（CML）的一线治疗方法，显示出很高的成功率。然而，观察到长期无治疗缓解（TFR）的患者数量较少。伊马替尼停药后分子复发在 24 个月时为 50%，80%发生在停药后 6 个月内。复发的原因之一是由于估计疾病水平极低或无法检测到疾病时存在较大误差而导致 TKI 过早停药，因此需要新的 CML 生物标志物。
使用下一代测序（NGS）来鉴定接受 TKI 治疗的 CML 成年患者分子反应中的 microRNAs（miRNAs）。共收集了 86 个样本，其中 30 个来自对伊马替尼治疗有反应的 CML 患者，28 个来自对伊马替尼治疗无反应的患者，28 个来自献血者。进行了 NGS，其中选择了 18 个 miRNA，并通过实时 RT-qPCR 进行了三次重复验证。
hsa-miR-181a-5p 在两个患者组中分别表达显著下调（p 值<0.05），下调倍数分别为 2.14 和 2.33 倍，而 hsa-miR-182-5p 和 hsa-miR-26a-5p 仅在无反应组中表达显著上调，上调倍数分别为 2.08 和 2.39 倍。这种下调与 TKI 治疗的患者 BCR-ABL1 数量减少一致。上调与 TKI 治疗的 CML 患者中大量存在 BCR-ABL1 一致。
因此，这些 miRNA 有可能成为 TKI 治疗分子反应的成年 CML 患者 BCR-ABL1 状态的新治疗生物标志物。这可以改进当前的方法，并需要进一步分析以寻找这些 miRNA 在 CML 中的靶点。
