Imataki Osamu, Ishida Tomoya, Kubo Hiroyuki, Uemura Makiko, Nanya Yasuhito, Kawakami Kimihiro, Ogawa Seishi, Kadowaki Norimitsu
Division of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Kagawa University Hospital Post Graduate Clinical Education Center, Kagawa, Japan.
Case Rep Oncol. 2020 Apr 22;13(1):449-455. doi: 10.1159/000506452. eCollection 2020 Jan-Apr.
Hematological malignancies, including chronic myeloid leukemia (CML), exhibit mutations; however, the function and molecular mechanism of these mutations remain unclear. was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, mutations have been associated with poor prognosis; however, the impact of mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed mutations. Physiologically, contributes to epigenetic regulation. In the CML-CP patient in this case report, mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of for CML is underscored. And the treatment strategy of CML with mutation has not been established. A discussion of this case was expected to facilitate treatment options.
血液系统恶性肿瘤，包括慢性髓性白血病（CML），存在突变；然而，这些突变的功能和分子机制仍不清楚。最初被鉴定为肿瘤抑制基因，其功能丧失会导致骨髓增生异常综合征（MDS）。突变在包括MDS、急性髓性白血病以及同样在CML等髓系恶性肿瘤中很常见且与疾病进展相关。在MDS中，突变与不良预后相关；然而，CML中突变的影响尚未得到充分描述。一名31岁男性被诊断为CML慢性期（CP）。实验室检查结果显示白细胞计数为187,200/µL，伴有无症状脾肿大。外周血原始细胞计数为5.0%，骨髓中为7.3%。染色体分析除t(9;22)(q34;q11.2)外无其他染色体异常。发病时，Sokal评分为1.4，表明为高危。患者接受酪氨酸激酶抑制剂（TKI）治疗，包括尼罗替尼约600毫克/天、博舒替尼约600毫克/天、波纳替尼约45毫克/天和达沙替尼约100毫克/天。然而，持续TKI治疗1.5年后，最佳结果是血液学反应。尽管在TKI治疗前和治疗期间反复分析了额外的染色体畸变和激酶突变，但未检测到已知的基因异常。此后，患者接受了来自HLA 7/8匹配的无关供体（HLA-Cw 1位点不匹配，移植物抗宿主方向）的骨髓移植。患者在移植后18天实现中性粒细胞植入，导致完全缓解，mRNA水平检测不到。然而，患者在121天后死于移植物抗宿主病和血栓性微血管病。对其干细胞移植前的CML细胞进行基因序列分析发现了突变。从生理上讲，有助于表观遗传调控。在本病例报告的CML-CP患者中，突变通过不明的耐药机制赋予对TKI的耐药性。尽管CML中突变导致TKI耐药的分子机制仍不清楚，但表观遗传调控是CML疾病进展的一种合理模式。强调了对CML的临床影响包括预后。并且尚未确立针对突变型CML的治疗策略。对该病例的讨论有望促进治疗选择。
