CCAAT增强子结合蛋白A（CEBPA）是调节血液发育过程中髓系分化和造血干祖细胞活性的关键转录因子之一。CEBPA基因突变常见于急性髓系白血病（AML）中,最近研究表明CEBPA bZIP框内单位点和经典双等位基因突变AML患者均具有类似的临床特征,已被单独划分为AML亚群。CEBPA bZIP框内突变而非传统的双等位CEBPA基因突变成为AML良好预后的分子指标,表明其在AML疾病进展和治疗预后中的重要性和特殊性。本文将从CEBPA蛋白在血液系统中的功能、CEBPA bZIP框内突变AML的临床特征与分子作用机制、以及伴CEBPA突变AML的治疗现状等方面进行综述,为进一步研究CEBPA bZIP框内突变在AML中的致病性和精准治疗新药物开发提供参考。
CCAAT enhancer-binding protein A（CEBPA）is one of the key transcription factors regulating myeloid differentiation and hematopoietic stem/progenitor cell maintenance during hematopoiesis．CEBPA gene mutations are commonly found in acute myeloid leukemia（AML）．Recent studies have demonstrated that AML patients haboring single CEBPA bZIP in-frame mutations or classical bi-allelic CEBPA mutations show similar clinical features and it has been individually classified as AML subgroup．Additionally,it is CEBPA bZIP in-frame mutations rather than the traditional biallelic CEBPA mutations that have emerged as a molecular indicator of favorable prognosis for clinical AML management,suggesting its importance and specificity in AML disease progression and therapeutic prognosis．Here,we reviewed serval aspects including the hematopoietic function of CEBPA protein,the clinical features and molecular mechanisms of AML with CEBPA bZIP in-frame mutations,and the current status of the treatment of AML with CEBPA mutations,which will provide a reference for further study of the pathogenicity of CEBPA bZIP in-frame mutations in AML and the development of new drugs for precision therapy．
血友病是一种由于X染色体上凝血因子基因突变所致的遗传性出血性疾病,目前主要的治疗方法是凝血因子替代疗法。但长期频繁的注射用药往往导致患者依从性差,容易产生抑制性抗体,从而影响治疗效果。虽然现在延长半衰期的新型凝血因子药物、人源化双特异性抗体以及抗组织因子途径抑制剂单克隆抗体等用于疾病治疗,在给药方式和作用持续时间上已有很大进步,但它们仍无法治愈血友病。因此,以疾病根治为重要目标的基因治疗被设计出来,近年来受到了广泛的关注。该文介绍了血友病基因治疗的原理、基因治疗载体的选择、基因治疗预处理方案,总结了现阶段基因治疗临床应用的安全性和有效性;最后讨论基因治疗目前存在的问题以及未来发展方向。
Hemophilia is a genetic bleeding disorder resulting from mutations in coagulation factor genes on the X chromosome．The mainstay of current treatment is coagulation factor replacement therapy．However,frequent and long-term injections often lead to poor patient compliance,easy inhibitor development,and compromised therapeutic efficacy．Despite advancements in delivery methods and prolonged action of novel agents such as extended half-life coagulation factor concentrates,humanized bispecific antibodies,and anti-tissue factor pathway inhibitor monoclonal antibodies,these approaches still fall short of curing hemophilia．Consequently,gene therapy,aiming for disease eradication,has garnered significant attention in recent years．This review delves into the principles of gene therapy,the selection of gene therapy vectors,and gene therapy preconditioning regimens．It summarizes the safety and efficacy of gene therapy in current clinical applications and discusses challenges and future directions in this field．
目的 探讨慢性淋巴细胞白血病（CLL）合并第二肿瘤临床特征和预后。方法 回顾性分析2015年8月—2021年10月我院收治的58例CLL患者,其中有11例合并第二肿瘤,47例无合并第二肿瘤,分析两组病例的临床特征及其对预后的影响。结果 CLL合并第二肿瘤和无合并第二肿瘤患者在年龄、性别、白细胞计数、血红蛋白水平、淋巴细胞计数、血小板计数、乳酸脱氢酶（LDH）、β2-微球蛋白（β2-MG）水平、分期、单个基因缺失类型之间比较差异无统计学意义,但CLL合并第二肿瘤患者基因缺失个数较无合并第二肿瘤CLL患者组高（χ2=11.17,P=0.03）,且总生存期较短。结论 CLL合并第二肿瘤患者常伴有多个基因缺失,且预后差,当CLL患者伴有多个基因缺失时,在诊治过程中需警惕有无合并第二肿瘤。
Objective To investigate the prognosis and clinical characteristics of chronic lymphocytic leukemia（CLL）patients with second tumor．Methods A retrospective analysis was performed on 58 cases of CLL patients who were diagnosed in our hospital from August 2015 to October 2021．The clinical data of 11 CLL patients with second cancer and 47 CLL patients without second cancer were compared and analyzed．Results There were no significant differences in age,sex,white blood cell count,lymphocyte count,platelet count,the level of serum β2-microglobulin and lactate dehydrogenase between two groups．However,in CLL patients with second cancer,the incidence of multiple genetic deletions was higher than those without second cancer（χ2 =11.17,P =0.03）．The overall survival time was shorter in CLL patients with second primary cancer．Conclusions CLL patients with second tumor have a frequent multiple gene deletions and poor prognosis．Physicians should pay attention to second cancers when diagnosing the CLL patients with multiple gene deletions．
目的 探讨单倍体亲缘异基因造血干细胞移植治疗重型再生障碍性贫血(SAA)的可行性。方法 对1例诊断SAA 4年余,先后经CsA治疗、脐血移植治疗均无效并反复输注红细胞、血小板的12岁男性患者进行单倍体亲缘异基因造血干细胞移植,供者为其胞兄,高分辨HLA基因型5/10相合,预处理方案为BU+CTX+ATG:BU 3.2 mg/kg×2 d,CTX 50 mg/kg×4 d,ATG 2.5 mg/kg×4 d。干细胞来源为G-CSF动员的骨髓+外周造血干细胞,共计输注单个核细胞(MNC)4.055×108/kg(受者体重),CD 34 2.331×106/kg。GVHD预防:-1 d采用与受者HLA部分相合的第三方脐带血细胞,术后联合应用环孢素A、短程氨甲碟呤、霉酚酸酯。结果 造血缓慢重建,术后22天(+22 d)ANC>0.5×109/L,术后3月血小板脱离输注。+26天DNA指纹图全部表现为供者基因型。+40天血型转为供者型“O”型。+29 d出现急性移植物抗宿主病aGVHD(胃肠型,Ⅲ度),+31 d、+34 d及+42 d予巴利昔单抗20 mg静滴,+40 d、+44 d、+63 d输注间充质干细胞,患者急性GVHD逐渐控制。期间曾出现肺部感染、口腔黏膜炎及巨细胞病毒血症,经抗感染后可控制。现随访3年,血象正常稳定,Kamofsky评分100分。结论 单倍体亲缘异基因造血干细胞移植治疗SAA,对无相合供者(包括亲缘或非亲缘)且强效免疫抑制治疗失败的患者,可考虑进行,GVHD和感染为主要并发症,需根据患者病情采用相应措施。
Objective To investigate the feasibility of haploid genetic allogeneic hematopoietic stem cell transplantation in the treatment of severe aplastic anemia(SAA) in our hospital. Methods A 12-year-old patient with acquired SAA for 4 years showed no response to CsA and cord blood transplant treatment and was transfusion-dependent. Lacking an HLA-identical sibling donor, the patient was treated with HSCT from his brother 5/10 matched at the generic level. Theconditioning regimen was BU+CTX+ATG:BU 3.2 mg/kg×2 d,CTX 50 mg/kg×4 d,ATG 2.5 mg/kg×4 d. Stem cells were the source of G-CSF mobilization of bone marrow and peripheral blood stem cells, dose of stem cells infused: mononuclear cells (MNC) 4.055×108/kg (body weight of subject), CD34 2.331×106/kg. Prevention of GVHD: -1 d Third-party umbilical cord blood cells which were HLA partially matched were used. Postoperative joint use included cyclosporine A, short-course methotrexate, mycophenolate mofetil. Results Hematopoiesis was slowly rebuilding, 22 d after surgery (+22 d) ANC> 0.5×109/L, after three months departing from transfusion of platelets. +26 d suggesting that the DNA fingerprints showed donor genotypes. +40 d into donor blood type “O” type. + 29 d occurred acute GVHD (GI type, Ⅲ degrees), + 31 d, + 34 d + 42 d infusion of basiliximab 20mg, + 40 d, + 44 d, + 63 d infusion of mesenchymal stem cells. Gradually acute GVHD was controlled in the patient, who had lung infections, oral mucositis and cytomegalovirus viremia, could be controlled with anti-infective. Now followed up for 3 years, hemogram change has been normal and stable. Kamofsky score was 100 points. Conclusion It may be considered to have haploid genetic allogeneic hematopoietic stem cell transplantation for treatment of SAA, for those patients who have non-matched donor (including relatives and non-relatives) and potent immunosuppressive therapy failure. GVHD and infection are major complications. Need to adopt appropriate measures in accordance with the patient's condition.
CCAAT增强子结合蛋白A（CEBPA）是调节血液发育过程中髓系分化和造血干祖细胞活性的关键转录因子之一。CEBPA基因突变常见于急性髓系白血病（AML）中，最近研究表明CEBPA bZIP框内单位点和经典双等位基因突变AML患者均具有类似的临床特征，已被单独划分为AML亚群。CEBPA bZIP框内突变而非传统的双等位CEBPA基因突变成为AML良好预后的分子指标，表明其在AML疾病进展和治疗预后中的重要性和特殊性。本文将从CEBPA蛋白在血液系统中的功能、CEBPA bZIP框内突变AML的临床特征与分子作用机制、以及伴CEBPA突变AML的治疗现状等方面进行综述，为进一步研究CEBPA bZIP框内突变在AML中的致病性和精准治疗新药物开发提供参考。
CAAT enhancer-binding protein A（CEBPA）is one of the key transcription factors regulating myeloid differentiation and hematopoietic stem/progenitor cell maintenance during hematopoiesis．CEBPA gene mutations are commonly found in acute myeloid leukemia（AML）．Recent studies have demonstrated that AML patients haboring single CEBPA bZIP in-frame mutations or classical bi-allelic CEBPA mutations show similar clinical features and it has been individually classified as AML subgroup．Additionally，it is CEBPA bZIP in-frame mutations rather than the traditional biallelic CEBPA mutations that have emerged as a molecular indicator of favorable prognosis for clinical AML management，suggesting its importance and specificity in AML disease progression and therapeutic prognosis．Here，we reviewed serval aspects including the hematopoietic function of CEBPA protein，the clinical features and molecular mechanisms of AML with CEBPA bZIP in-frame mutations，and the current status of the treatment of AML with CEBPA mutations，which will provide a reference for further study of the pathogenicity of CEBPA bZIP in-frame mutations in AML and the development of new drugs for precision therapy．
