儿童急性早幼粒细胞白血病的临床及相关诱导性多能干细胞研究
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摘要
急性早幼粒细胞白血病(APL)是急性髓细胞白血病(AML)中较少见的一种类型,是以骨髓中异常早幼粒细胞增多、临床以凝血异常性出血为特征,早幼粒细胞白血病基因(PML)和维A酸受体a (RARa)基因相互融合形成PML/RARa基因为APL的发病基础,也是分子靶向治疗的基础。以全反式维甲酸(ATRA)、砷剂(例如三氧化二砷,ATO)为基础的联合蒽环类化疗药组成的治疗方案已经成为目前儿童APL的主流治疗方案,使得儿童APL患者的长期生存率提高到70%以上,已经成为一种仅通过药物即可治愈的恶性血液病。而蒽环类化疗药引起的心脏和肝脏损伤等副作用以及疾病早期死亡仍然是儿童APL治疗的一大挑战。国内外有关儿童APL的报道有限,目前尚无针对儿童APL患者的国际统一标准治疗方案。为了在提高疗效的基础上进一步降低或者消除ATRA、 ATO的不良反应,减少蒽环类化疗药的用量并降低儿童APL的复发,选择合适的治疗方案和剂量,大样本量回顾性及前瞻性儿童APL临床研究显得尤为重要。
虽然儿童APL患者的长期生存率在近30年明显提高,但是中国目前还是发展中国家,部分儿童APL患者家庭因经济和受教育程度等因素的影响而放弃治疗,这成为我国儿童APL治疗失败的重要组成部分。回顾性分析儿童APL患者放弃治疗的原因,对于合理化治疗方案的制定,提高患儿及家属对本病的认识,推广儿童医疗保健及建立相应的社会保障体系、降低儿童APL治疗失败率并提高长期生存率意义重大。
复发与诱导缓解失败仍然是目前儿童白血病治疗的难题,而造血干细胞移植目前是唯一有可能治愈此类儿童的补救治疗手段。但造血干细胞的来源、配型与排斥仍是目前未完全解决的问题,因此探索性研究并寻找排斥性小、来源丰富的造血干细胞已经成为当今国际血液学领域探索的热点。诱导性多能干细胞(induced pluripotent stem cells, iPS细胞)具有发育成多种细胞的能力,它是通过在分化成熟的体细胞中转染入几个特定的转录因子以诱导体细胞重编程,获得可以不断自我更新与多向分化潜能的细胞。血液系统恶性肿瘤病人携带突变细胞来源的iPS细胞,这对于白血病发病机制的研究、药物筛选、选择细胞及基因治疗具有重大意义,取自病人无突变皮肤细胞来源的iPS细胞若能分化为造血干细胞,将为其自身移植提供丰富可靠的细胞来源。
本文回顾性分析了儿童较少见的一种急性白血病APL的临床特征、不同治疗方案及预后比较,同时对部分放弃治疗的原因进行分析,目的在于优化儿童APL的治疗方案,结合中国国情从家庭经济学方面降低儿童APL的放弃治疗率,由此降低儿童APL的治疗失败率,提高其长期生存率,同时通过iPS细胞的技术研究探索其在白血病治疗中应用的可能性。
第一部分四种化疗方案治疗119例儿童急性早幼粒细胞白血病
研究目的：探讨以全反式维甲酸(ATRA)为基础的四种化疗方案治疗儿童急性早幼粒细胞白血病(APL)的临床疗效和预后。研究方法：收集并分析1997年7月至2008年12月收治于我国中南部6大综合及专科医院儿科血液病房初诊APL患儿的临床资料,四种化疗方案分别为：方案1为内部方案(protocol developed in house);方案2为PETHEMALPA99修改方案(modified from the PETHEMALPA99);方案3为欧洲APL93修改方案(modified from the europen-APL93);方案4为英国血液委员会推荐标准方案(British Committee for Standards).研究结果：统计结果显示四种方案相对应的完全缓解率(CR)分别为88.9%、87.5%、97.1%和87.5%,无统计学差异。但方案2和方案3具有更高的3.5年无病生存率（3.5-DFS)、更低的复发率、药物毒性(包括肝脏、心脏毒性和维甲酸综合征)和感染发生率，具有统计学意义（p<0.05)。结论：方案2和方案3治疗初诊儿童APL患者能提高总体临床疗效和预后，可能由于其包含特殊的药物组成有关。
第二部分儿童急性早幼粒细胞白血病放弃治疗的原因探讨
研究背景和目的：放弃治疗是儿童急性早幼粒白血病(APL)治疗失败的重要原因,特别是在发展中国家,这与患儿家长的社会经济学因素密切相关。此研究旨在进一步探讨儿童APL患者放弃治疗的原因及如何降低治疗失败率。研究方法：成功收集与随访158例1997年9月至2008年12月来自中山大学附属第一、第二医院,广东省广州市儿童医院,广东省人民医院,以及华中科技大学同济医学院附属同济医院、协和医院的初诊儿童APL临床病例,随访并回顾性研究和分析放弃治疗的具体原因。研究结果：158例病例中有39例(24.5%)放弃治疗,39例放弃治疗患者中的37例(94.9%)成功随访并研究分析,放弃的原因主要与经济困难、相信APL无法治愈、女孩、年龄小于5岁和父母受教育水平低(P＜0.05)有关。结论：为了降低儿童APL的治疗失败率,需要推广儿童医疗保健及建立相应的社会保障体系、提高患儿及家属对本病的认识,并在医护人员与患者家属间建立全面充分沟通,以及整个社会人口素质水平的全面提高。
第三部分儿童白血病诱导性多能干细胞的建立与造血分化
研究目的：将携带罗伯逊易位[Rob(13；22)]的白血病患者的皮肤细胞重编程,构建诱导性多能干(iPS)细胞株并使其向造血细胞分化,研究该细胞株能否在裸鼠体内重建造血,产生白血病以及罗伯逊易位在其发病中的作用。研究方法：以携带Rob(13；22)的一岁女性急性髓细胞白血病患者的皮肤成纤维细胞为亲代细胞(命名为TC细胞),用分别携带OCT4, SOX2, KLF4, C-MYC, NANOG和LIN28基因的5种慢病毒感染TC细胞,使其重编程为人诱导性多潜能干细胞(iPS)株(命名为TZ4)；并用免疫荧光法检验TZ4iPS细胞膜表面标记SSEA3和SSEA4、在免疫缺陷裸鼠肌肉注射TZ4细胞致畸胎瘤的形成来检测其干细胞的多能性；核型分析比较TZ4与其亲代TC细胞的染色体变异；体外诱导TZ4分化为血液血管母(HB)细胞,流式细胞分析检测诱导分化的HB细胞表面标志CD34和CD45,并用HB细胞尾静脉注射亚致死剂量照射的裸鼠观察其能否在体内重建造血。研究结果：TZ4iPS细胞被成功建立,具有多能干细胞的特性(表达多能性表面标志SSEA3、SSEA4,并能形成畸胎瘤),核型分析结果显示：TC和TZ4的核型均保留了Rob(13;22), TZ4核型为46,XX,+5,Rob(13;22)(q10;q10), TZ4被成功诱导分化为HB细胞,流式细胞分析结果显示HB细胞标志CD34、造血干细胞标志CD45,将HB细胞静脉注射亚致死剂量照射的裸鼠后未见造血和白血病形成。结论：罗伯逊易位Rob(13；22)的白血病患者的皮肤成纤维细胞能重编程为iPS细胞,该iPS细胞具有多能干细胞的特性；其核型发生了变异,但是仍旧保留了与特征性的亲代皮肤成纤维细胞相同的核型Rob(13;22)(q10;q10);该iPS细胞具有诱导分化的能力,能被成功诱导分化为血液血管母细胞；但体内实验未见造血重建和白血病发生,该体内实验方法有待进一步探索。
Part1Retrospective Analysis of119Cases of Pediatric Acute Promyelocytic Leukemia:Comparisons of four Regimes
Objective:Clinical trials have demonstrated that pediatric Acute promyelocytic leukemia (APL) is highly curable. Small-scale studies have been reported on treatment of APL on one or two treatment regimes. Here we report a multiple center-based study of119cases of pediatric APL treated with four regimes based on all trans-retinoic acid (ATRA). Procedures:We retrospectively analyzed the clinical and laboratorial characteristics and treatment outcome of the pediatric APL patients. Regime1used a protocol developed in house, regime2was modified from the PETHEMA LPA99protocol, regime3was modified from the European-APL93protocol, and regime4used a protocol suggested by the British Committee for Standards. Results:the overall complete remission rates for the four regimes were88.9%,87.5%,97.1%, and87.5%, respectively, which have no statistic difference. However, better results were observed with regimes2and3than regimes1and4, in terms of estimated3.5-year disease-free survivals, relapse rates, drug toxicity (including hepatotoxicity, cardiac arrhythmia, and differentiation syndrome), and sepsis. Conclusion:The overall outcomes are better with regimes2and3than with regimes1and4, which may benefit from the specific compositions of regimes2and3.
Part2Case study of pediatric acute promyelocytic leukemia:why did some patients abandon treatment?
Background:Treatment refusal and abandonment are major causes for death of pediatric acute promyelocytic leukemia (APL) patients, especially in developing countries, which is often associated with the socioeconomic status of patient's parents. Here we report the reasons identified for refusal and abandonment of pediatric APL treatment in six hospitals in central and southern China. Methods:we retrospectively analyzed the medical records of pediatric APL patients admitted from September1997to December2009, and interviewed the families of those who refused or abandoned the treatment to identify reasons associated to the dropout. Results:Of158admitted patients in total,39(23.7%) refused or abandoned treatment. Interviews were successfully conducted through telephone or mail with the parents or guardians of37of the dropout patients. The reasons for the dropout, although varying among these cases, are associated with financial hardships, misbelief that APL is incurable, the female gender, age younger than5years, and parents'educational levels. Conclusion:Effective health insurance systems, sufficient and adequate communications between health care providers and patients/parents, legal protection from discrimination against female and young patients, educational programs for patients/parents, and psychosocial support from communities are essential to reduce the treatment refusal and abandonment, and increase the survival and quality life of pediatric APL patients.
Part3Generation and hematopoietic differentiation of induced pluripotent stem cells from a pediatric leukemia patient
Objective:the purpose of this study is to derive induced pluripotent stem (iPS) cells from the skin fibroblasts of a leukemia patient, to differentiate the iPS cells into hematopoietic stem/progenitor cells, and to reconstitute the hematopoietic system and model leukemogenesis in sublethally irradiated nude mice. Methods:we used the skin fibroblasts from a one-year-old, acute myeloid leukemia, female patient with Rob(13;22) as parental cells named TC. Transduction of TC with lentiviral vectors expressing OCT4, SOX2, KLF4, C-MYC, NANOG, and LIN28was performed to derive iPS cells. An established iPS cell line from this patient was named TZ4. Fluoroimmunoassay for expression of the pluripotency markers SSEA3and SSEA4, and teratomas formation assay were used to confirm the pluripotency of TZ4. Karyotyping of the TC fibroblasts and TZ4iPSCs was conducted. The TZ4and a wild-type iPSC line TK5were induced to differentiate into hemangioblasts (HBs), which were subjected to flow cytometry analysis for CD34+and CD45+cell ratios. The HB cells differentiated from TZ4or TK5iPS cells were injected intravenously through the tail vein into sublethally irradiated NOG-SCID (immunocompromised) mice to observe hematopoietic reconstitution and leukemogenesis. Results:An iPS cell line TZ4was successfully derived from the skin fibroblasts of the patient. The pluripotency of TZ4was confirmed for expression of the pluripotency markers SSEA3and SSEA4, and the capability of teratoma formation. The karyotyping showed that the dominant karyotypes of TC and TZ4were mainly contained Rob(13;22), which TZ4tested as46, XX,+5, Rob(13;22)(q10;q10), respectively. Both TZ4and TK5iPS cells could differentiate into hemangiobloasts (HBs), progenitors for both hematopoietic and angiogenic cells. The HBs differentiated from TZ4and TK5contained similar ratio of CD34+and CD45+cells based on flow cytometry analysis. However, following transplantation of the HBs into sublethally irraidated NOG-SCID mice, no human cell engraftment was observed in the mice. Conclusions:Fibroblasts with Rob(13;22) karyotype from a pediatric AML patient could be reprogrammed to generate iPS cells, which sustained the Rob(13;22) karyotype with some additional chromosomal abnormalities. Like wild-type iPS cells, the patient-derived iPS cells could also differentiate into HB cells. However, in vivo experiments on sublethally irraidated NOG-SCID mice did not show engraftment of the human iPS cell-derived HB cells. Further studies are necessary to further characterize the HB cells and optimize the methodologies for blood reconstitution in mice with the human HB cells.
虽然儿童APL患者的长期生存率在近30年明显提高,但是中国目前还是发展中国家,部分儿童APL患者家庭因经济和受教育程度等因素的影响而放弃治疗,这成为我国儿童APL治疗失败的重要组成部分。回顾性分析儿童APL患者放弃治疗的原因,对于合理化治疗方案的制定,提高患儿及家属对本病的认识,推广儿童医疗保健及建立相应的社会保障体系、降低儿童APL治疗失败率并提高长期生存率意义重大。
复发与诱导缓解失败仍然是目前儿童白血病治疗的难题,而造血干细胞移植目前是唯一有可能治愈此类儿童的补救治疗手段。但造血干细胞的来源、配型与排斥仍是目前未完全解决的问题,因此探索性研究并寻找排斥性小、来源丰富的造血干细胞已经成为当今国际血液学领域探索的热点。诱导性多能干细胞(induced pluripotent stem cells, iPS细胞)具有发育成多种细胞的能力,它是通过在分化成熟的体细胞中转染入几个特定的转录因子以诱导体细胞重编程,获得可以不断自我更新与多向分化潜能的细胞。血液系统恶性肿瘤病人携带突变细胞来源的iPS细胞,这对于白血病发病机制的研究、药物筛选、选择细胞及基因治疗具有重大意义,取自病人无突变皮肤细胞来源的iPS细胞若能分化为造血干细胞,将为其自身移植提供丰富可靠的细胞来源。
本文回顾性分析了儿童较少见的一种急性白血病APL的临床特征、不同治疗方案及预后比较,同时对部分放弃治疗的原因进行分析,目的在于优化儿童APL的治疗方案,结合中国国情从家庭经济学方面降低儿童APL的放弃治疗率,由此降低儿童APL的治疗失败率,提高其长期生存率,同时通过iPS细胞的技术研究探索其在白血病治疗中应用的可能性。
第一部分四种化疗方案治疗119例儿童急性早幼粒细胞白血病
研究目的：探讨以全反式维甲酸(ATRA)为基础的四种化疗方案治疗儿童急性早幼粒细胞白血病(APL)的临床疗效和预后。研究方法：收集并分析1997年7月至2008年12月收治于我国中南部6大综合及专科医院儿科血液病房初诊APL患儿的临床资料,四种化疗方案分别为：方案1为内部方案(protocol developed in house);方案2为PETHEMALPA99修改方案(modified from the PETHEMALPA99);方案3为欧洲APL93修改方案(modified from the europen-APL93);方案4为英国血液委员会推荐标准方案(British Committee for Standards).研究结果：统计结果显示四种方案相对应的完全缓解率(CR)分别为88.9%、87.5%、97.1%和87.5%,无统计学差异。但方案2和方案3具有更高的3.5年无病生存率（3.5-DFS)、更低的复发率、药物毒性(包括肝脏、心脏毒性和维甲酸综合征)和感染发生率，具有统计学意义（p<0.05)。结论：方案2和方案3治疗初诊儿童APL患者能提高总体临床疗效和预后，可能由于其包含特殊的药物组成有关。
第二部分儿童急性早幼粒细胞白血病放弃治疗的原因探讨
研究背景和目的：放弃治疗是儿童急性早幼粒白血病(APL)治疗失败的重要原因,特别是在发展中国家,这与患儿家长的社会经济学因素密切相关。此研究旨在进一步探讨儿童APL患者放弃治疗的原因及如何降低治疗失败率。研究方法：成功收集与随访158例1997年9月至2008年12月来自中山大学附属第一、第二医院,广东省广州市儿童医院,广东省人民医院,以及华中科技大学同济医学院附属同济医院、协和医院的初诊儿童APL临床病例,随访并回顾性研究和分析放弃治疗的具体原因。研究结果：158例病例中有39例(24.5%)放弃治疗,39例放弃治疗患者中的37例(94.9%)成功随访并研究分析,放弃的原因主要与经济困难、相信APL无法治愈、女孩、年龄小于5岁和父母受教育水平低(P＜0.05)有关。结论：为了降低儿童APL的治疗失败率,需要推广儿童医疗保健及建立相应的社会保障体系、提高患儿及家属对本病的认识,并在医护人员与患者家属间建立全面充分沟通,以及整个社会人口素质水平的全面提高。
第三部分儿童白血病诱导性多能干细胞的建立与造血分化
研究目的：将携带罗伯逊易位[Rob(13；22)]的白血病患者的皮肤细胞重编程,构建诱导性多能干(iPS)细胞株并使其向造血细胞分化,研究该细胞株能否在裸鼠体内重建造血,产生白血病以及罗伯逊易位在其发病中的作用。研究方法：以携带Rob(13；22)的一岁女性急性髓细胞白血病患者的皮肤成纤维细胞为亲代细胞(命名为TC细胞),用分别携带OCT4, SOX2, KLF4, C-MYC, NANOG和LIN28基因的5种慢病毒感染TC细胞,使其重编程为人诱导性多潜能干细胞(iPS)株(命名为TZ4)；并用免疫荧光法检验TZ4iPS细胞膜表面标记SSEA3和SSEA4、在免疫缺陷裸鼠肌肉注射TZ4细胞致畸胎瘤的形成来检测其干细胞的多能性；核型分析比较TZ4与其亲代TC细胞的染色体变异；体外诱导TZ4分化为血液血管母(HB)细胞,流式细胞分析检测诱导分化的HB细胞表面标志CD34和CD45,并用HB细胞尾静脉注射亚致死剂量照射的裸鼠观察其能否在体内重建造血。研究结果：TZ4iPS细胞被成功建立,具有多能干细胞的特性(表达多能性表面标志SSEA3、SSEA4,并能形成畸胎瘤),核型分析结果显示：TC和TZ4的核型均保留了Rob(13;22), TZ4核型为46,XX,+5,Rob(13;22)(q10;q10), TZ4被成功诱导分化为HB细胞,流式细胞分析结果显示HB细胞标志CD34、造血干细胞标志CD45,将HB细胞静脉注射亚致死剂量照射的裸鼠后未见造血和白血病形成。结论：罗伯逊易位Rob(13；22)的白血病患者的皮肤成纤维细胞能重编程为iPS细胞,该iPS细胞具有多能干细胞的特性；其核型发生了变异,但是仍旧保留了与特征性的亲代皮肤成纤维细胞相同的核型Rob(13;22)(q10;q10);该iPS细胞具有诱导分化的能力,能被成功诱导分化为血液血管母细胞；但体内实验未见造血重建和白血病发生,该体内实验方法有待进一步探索。
Part1Retrospective Analysis of119Cases of Pediatric Acute Promyelocytic Leukemia:Comparisons of four Regimes
Objective:Clinical trials have demonstrated that pediatric Acute promyelocytic leukemia (APL) is highly curable. Small-scale studies have been reported on treatment of APL on one or two treatment regimes. Here we report a multiple center-based study of119cases of pediatric APL treated with four regimes based on all trans-retinoic acid (ATRA). Procedures:We retrospectively analyzed the clinical and laboratorial characteristics and treatment outcome of the pediatric APL patients. Regime1used a protocol developed in house, regime2was modified from the PETHEMA LPA99protocol, regime3was modified from the European-APL93protocol, and regime4used a protocol suggested by the British Committee for Standards. Results:the overall complete remission rates for the four regimes were88.9%,87.5%,97.1%, and87.5%, respectively, which have no statistic difference. However, better results were observed with regimes2and3than regimes1and4, in terms of estimated3.5-year disease-free survivals, relapse rates, drug toxicity (including hepatotoxicity, cardiac arrhythmia, and differentiation syndrome), and sepsis. Conclusion:The overall outcomes are better with regimes2and3than with regimes1and4, which may benefit from the specific compositions of regimes2and3.
Part2Case study of pediatric acute promyelocytic leukemia:why did some patients abandon treatment?
Background:Treatment refusal and abandonment are major causes for death of pediatric acute promyelocytic leukemia (APL) patients, especially in developing countries, which is often associated with the socioeconomic status of patient's parents. Here we report the reasons identified for refusal and abandonment of pediatric APL treatment in six hospitals in central and southern China. Methods:we retrospectively analyzed the medical records of pediatric APL patients admitted from September1997to December2009, and interviewed the families of those who refused or abandoned the treatment to identify reasons associated to the dropout. Results:Of158admitted patients in total,39(23.7%) refused or abandoned treatment. Interviews were successfully conducted through telephone or mail with the parents or guardians of37of the dropout patients. The reasons for the dropout, although varying among these cases, are associated with financial hardships, misbelief that APL is incurable, the female gender, age younger than5years, and parents'educational levels. Conclusion:Effective health insurance systems, sufficient and adequate communications between health care providers and patients/parents, legal protection from discrimination against female and young patients, educational programs for patients/parents, and psychosocial support from communities are essential to reduce the treatment refusal and abandonment, and increase the survival and quality life of pediatric APL patients.
Part3Generation and hematopoietic differentiation of induced pluripotent stem cells from a pediatric leukemia patient
Objective:the purpose of this study is to derive induced pluripotent stem (iPS) cells from the skin fibroblasts of a leukemia patient, to differentiate the iPS cells into hematopoietic stem/progenitor cells, and to reconstitute the hematopoietic system and model leukemogenesis in sublethally irradiated nude mice. Methods:we used the skin fibroblasts from a one-year-old, acute myeloid leukemia, female patient with Rob(13;22) as parental cells named TC. Transduction of TC with lentiviral vectors expressing OCT4, SOX2, KLF4, C-MYC, NANOG, and LIN28was performed to derive iPS cells. An established iPS cell line from this patient was named TZ4. Fluoroimmunoassay for expression of the pluripotency markers SSEA3and SSEA4, and teratomas formation assay were used to confirm the pluripotency of TZ4. Karyotyping of the TC fibroblasts and TZ4iPSCs was conducted. The TZ4and a wild-type iPSC line TK5were induced to differentiate into hemangioblasts (HBs), which were subjected to flow cytometry analysis for CD34+and CD45+cell ratios. The HB cells differentiated from TZ4or TK5iPS cells were injected intravenously through the tail vein into sublethally irradiated NOG-SCID (immunocompromised) mice to observe hematopoietic reconstitution and leukemogenesis. Results:An iPS cell line TZ4was successfully derived from the skin fibroblasts of the patient. The pluripotency of TZ4was confirmed for expression of the pluripotency markers SSEA3and SSEA4, and the capability of teratoma formation. The karyotyping showed that the dominant karyotypes of TC and TZ4were mainly contained Rob(13;22), which TZ4tested as46, XX,+5, Rob(13;22)(q10;q10), respectively. Both TZ4and TK5iPS cells could differentiate into hemangiobloasts (HBs), progenitors for both hematopoietic and angiogenic cells. The HBs differentiated from TZ4and TK5contained similar ratio of CD34+and CD45+cells based on flow cytometry analysis. However, following transplantation of the HBs into sublethally irraidated NOG-SCID mice, no human cell engraftment was observed in the mice. Conclusions:Fibroblasts with Rob(13;22) karyotype from a pediatric AML patient could be reprogrammed to generate iPS cells, which sustained the Rob(13;22) karyotype with some additional chromosomal abnormalities. Like wild-type iPS cells, the patient-derived iPS cells could also differentiate into HB cells. However, in vivo experiments on sublethally irraidated NOG-SCID mice did not show engraftment of the human iPS cell-derived HB cells. Further studies are necessary to further characterize the HB cells and optimize the methodologies for blood reconstitution in mice with the human HB cells.
引文
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