Abd Elrhman Heba E, Ebian Huda F
Department of Clinical Pathology and Chemical Pathology, Faculty of Medicine, Zagazig University Zagazig, Egypt.
Am J Blood Res. 2019 Jun 15;9(2):15-24. eCollection 2019.
The Hedgehog (Hh) pathway is stimulated by inactivating mutations of Patched Homolog 1 . There is accumulating evidence that Hh signaling plays a critical role in the pathogenesis of various haemopoietic malignancies. Particular interest has focused on the role of Hh signaling in chronic myeloid leukemia (CML). The Hh signaling is increased in BCR-ABL+ve progenitor cells and Hh signaling is further up regulated with disease progression.
The aim of this study was to determine the frequency and types of PTCH1 gene mutations in Chronic Myeloid Leukemia (CML) patients and to correlate the effect of these mutations on the prognosis and outcome of CML and for predicting the imatinib response in CML patients.
The study included fifty newly diagnosed CML patients and ten healthy volunteers (the control group) to verify the presence or absence of PTCH1 gene mutation. The patients were subjected to clinical examination, routine laboratory investigations, bone marrow examination, Cytogenetic evaluations of t(9;22) and molecular study of BCR-ABL fusion gene. All participants in this study were subjected to the assessment for the presence of PTCH1 gene mutation by DNA extraction followed by polymerase chain reaction (PCR) of genomic DNA corresponding to exon 23 of PTCH1 gene, purification of amplified PCR product, followed by sequencing analysis for detection of PTCH1 gene exon 23 mutations and the types of these mutations.
Four types of mutations of PTCH1 gene were detected in 24 CML patients (48%), three types of them were missence while the fourth type was frame shift mutation. There was no significant association between PTCH1 gene mutation and percent of BCR-ABL fusion genes at level less than 10% at 3 months of treatment, complete cytogenetic response (CCyR) at one year, disease free survival and overall survival. However there was significant association between PTCH1 gene mutation and imatinib failure (P=0.03).
PTCH1 gene mutation should be considered a promising molecular marker for predicting the probability of imatinib response in CML patients. Hedgehog pathway activation in CML patients can raise a possibility that combinations of ABL and Hh inhibitors might offer a new treatment strategy in CML and might help to effectively cure this disease.
刺猬信号通路（Hh）由patched同源蛋白1（Patched Homolog 1）的失活突变激活。越来越多的证据表明，Hh信号在各种造血系统恶性肿瘤的发病机制中起关键作用。人们尤其关注Hh信号在慢性髓性白血病（CML）中的作用。在BCR-ABL阳性祖细胞中Hh信号增强，且随着疾病进展Hh信号进一步上调。
本研究旨在确定慢性髓性白血病（CML）患者中PTCH1基因突变的频率和类型，并将这些突变对CML预后和结局的影响进行关联分析，以及预测CML患者对伊马替尼的反应。
本研究纳入50例新诊断的CML患者和10名健康志愿者（对照组），以验证PTCH1基因突变的有无。对患者进行临床检查、常规实验室检查、骨髓检查、t(9;22)的细胞遗传学评估以及BCR-ABL融合基因的分子研究。本研究的所有参与者均通过DNA提取进行PTCH1基因突变的评估，随后对对应于PTCH1基因第23外显子的基因组DNA进行聚合酶链反应（PCR），纯化扩增的PCR产物，随后进行测序分析以检测PTCH1基因第23外显子的突变及这些突变的类型。
在24例CML患者（48%）中检测到4种类型的PTCH1基因突变，其中3种为错义突变，第4种为移码突变。在治疗3个月时BCR-ABL融合基因水平低于10%、1年时的完全细胞遗传学反应（CCyR）、无病生存期和总生存期方面，PTCH1基因突变与这些指标之间无显著关联。然而，PTCH1基因突变与伊马替尼治疗失败之间存在显著关联（P = 0.03）。
PTCH1基因突变应被视为预测CML患者伊马替尼反应概率的一个有前景的分子标志物。CML患者中刺猬信号通路激活提示ABL和Hh抑制剂联合应用可能为CML提供一种新的治疗策略，并可能有助于有效治愈该疾病。
