Guru Sameer Ahmad, Mir Rashid, Bhat Musadiq, Najar Imtiyaz, Zuberi Mariyam, Sumi Mamta, Masroor Mirza, Gupta Naresh, Saxena Alpana
1 Maulana Azad Medical College, New Delhi, India.
2 Sher-i-Kashmir Institute of Medical Science, Srinagar, India.
Tumour Biol. 2017 Oct;39(10):1010428317713857. doi: 10.1177/1010428317713857.
Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2 ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p < 0.0001). Moreover, +68GA del/del and ins/del genotypes in imatinib-treated chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an allele dose-dependent manner. Platelet-derived growth factor receptor-α -909AA genotype is also associated with lower expression of platelet-derived growth factor receptor-α. The downregulation of platelet-derived growth factor receptor-α expression may play a causative role in imatinib-induced thrombocytopenia, a common side effect, in the subset of chronic myeloid leukemia patients with platelet-derived growth factor receptor-α +68 GA ins/del, +68 GA del/del, and -909C/A genotypes.
血小板衍生生长因子受体与许多恶性和非恶性疾病有关。血小板衍生生长因子受体-α是一种酪氨酸激酶，也是伊马替尼的次要作用靶点，伊马替尼是一种用于治疗慢性髓性白血病的革命性药物，显著提高了慢性髓性白血病患者的生存率。鉴于血小板衍生生长因子受体在血小板发育中的重要性及其被伊马替尼抑制，分析血小板衍生生长因子受体-α在慢性髓性白血病患者伊马替尼诱导的血小板减少症发生过程中与伊马替尼治疗的关系很有意思。我们假设血小板衍生生长因子受体-α基因启动子区域的两个已知功能多态性，即+68GA插入/缺失和-909C/A，可能会影响接受伊马替尼治疗的慢性髓性白血病患者发生血小板减少症的易感性。在印度新德里洛克纳亚克医院收治的一组慢性髓性白血病患者中进行了一项病例对照研究。研究了100例慢性期慢性髓性白血病患者和100例年龄及性别匹配的健康对照。开始伊马替尼治疗后，对慢性髓性白血病患者的血液学反应进行了2年的定期监测，其中血小板减少症的发生是主要终点。通过等位基因特异性聚合酶链反应研究血小板衍生生长因子受体-α启动子多态性+68GA ins/del和-909C/A。通过定量实时聚合酶链反应评估血小板衍生生长因子受体-α信使核糖核酸表达。信使核糖核酸表达结果以2±标准差表示。血小板减少性和非血小板减少性慢性髓性白血病患者组之间+68GA ins/del启动子多态性基因型的分布有显著差异（p<0.0001）。此外，伊马替尼治疗的慢性髓性白血病患者中+68GA del/del和ins/del基因型与发生血小板减少症的风险增加相关，比值比分别为6.5（95%置信区间=2.02-0.89，p=0.001）和6.0（95%置信区间=2.26-15.91，p=0.0002）。同样，血小板减少性和非血小板减少性慢性髓性白血病患者组之间-909C/A启动子多态性基因型分布也有显著差异（p=0.02），并且-909C/A多态性突变纯合子（AA）基因型与伊马替尼诱导的血小板减少症风险显著增加相关，比值比为7.7（95%置信区间1.50至39.91，p=0.009）。然而，未发现杂合子基因型（-909C/A）与伊马替尼诱导的血小板减少症有显著风险相关，比值比为1.9（95%置信区间=0.86-4.56，p=1.14）。与对照组相比，慢性髓性白血病患者的血小板衍生生长因子受体-α信使核糖核酸表达显著更高（p=0.008）。此外，与无血小板减少症的患者相比，伊马替尼诱导的血小板减少症患者的血小板衍生生长因子受体-α信使核糖核酸表达显著更低（p=0.01）。观察到血小板衍生生长因子受体-α信使核糖核酸表达在不同的+68 GA ins/del和-909C/A多态性基因型方面存在差异表达。+68GA缺失等位基因和-909A等位基因与血小板衍生生长因子受体-α信使核糖核酸表达降低显著相关。血小板衍生生长因子受体-α +68GA del/del、+68GA ins/del和-909AA基因型与伊马替尼治疗的慢性髓性白血病患者发生血小板减少症的风险增加相关。+68GA缺失等位基因以等位基因剂量依赖的方式伴随着血小板衍生生长因子受体-α信使核糖核酸表达显著降低。血小板衍生生长因子受体-α -909AA基因型也与血小板衍生生长因子受体-α表达降低相关。在具有血小板衍生生长因子受体-α +68 GA ins/del、+68 GA del/del和-909C/A基因型的慢性髓性白血病患者亚组中，血小板衍生生长因子受体-α表达的下调可能在伊马替尼诱导的血小板减少症（一种常见的副作用）中起致病作用。
