骨髓增生异常综合征基因突变与预后模型研究进展

骨髓增生异常综合征(MDS)是一种克隆性疾病,其特征是复杂的基因异常的积累,这些异常决定了疾病的表型、预后以及向急性髓系白血病转化的风险。不同表型的MDS患者临床表现和预后差异很大,总生存期在数月至数年不等。预后评分系统是重要的分层工具,目前的模型对于预测MDS患者预后非常有效,但这些模型的变量主要集中在骨髓和外周血分析,将基因突变添加到现有模型会提高整体预测能力。探寻将临床和基因组数据合并到一个复杂且高度精确模型中的最佳方法仍是一项正在进行中的工作,最终将建立一个全面的基因-临床模型,将基因组数据的使用转化为临床实践。文章结合第60届美国血液学会(ASH)年会相关报道就MDS的基因突变与预后模型研究进展进行综述。     

骨髓增生异常综合征基因突变模式及靶向治疗研究进展

骨髓增生异常综合征(MDS)是最常见的髓系肿瘤,其存在的克隆造血导致骨髓衰竭。对MDS基因突变谱的了解有助于理解MDS的生物学意义,并可用于疾病的早期诊断、精确的危度分层、解释发病机制和改进治疗方案。随着MDS病理学特征逐渐得到阐明,个体化高效治疗方案渐趋完善,靶向治疗将可能改善患者预后。文章介绍第60届美国血液学会(ASH)年会有关MDS基因突变及靶向治疗进展的内容。     

骨髓增生异常综合征患者基因突变情况分析

目的 分析骨髓增生异常综合征(MDS)患者的基因突变情况.方法 选择2016年1月至2017年7月中国中医科学院西苑医院初诊的47例MDS患者,采用NGS 127-gene panel检测基因突变,分析基因突变与临床特征的关系.结果47例MDS患者中,31例(66.0％)检测到基因突变,涉及有临床意义的突变基因23个,检出率>5％的基因共7个,由高到低依次为U2AF1(23.4％)、SF3B1(12.8％)、ASXL1(10.6％)、TET2(8.5％)、BCOR(8.5％)、TP53(8.5％)、DNMT3A(6.4％).31例基因突变患者中,16例(51.6％)存在2个以上基因协同突变,其中12例患者的协同基因突变存在于不同基因功能组内,高于单一基因功能组内的基因协同突变(4例).IDH2-KRAS、IDH2-SRSF2、IDH2-STAG2、KRAS-SRSF2、KRAS-STAG2、RUNX1-PHF6、EZH2-ASXL1、EZH2-ZRSR2、NPM1-NRAS基因之间有共存关系(均P<0.05).JAK2、KRAS、NRAS、SH2B3四个信号通路相关的变异等位基因频率(VAF)较低,处于亚克隆地位.1例JAK2突变见于MDS-U患者;1例SH2B3基因突变见于核型预后极高危患者;2例SETBP1以及2例EZH2突变均见于修订的国际预后评分系统(IPSS-R)预后高危患者.结论 MDS患者常见突变基因为U2AF1、SF3B1、ASXL1、TET2.不同基因功能组内的基因倾向于协同突变.基因突变可用于判断MDS患者预后,作为其治疗的靶点.     

骨髓增生异常综合征表观遗传学治疗进展

 表观遗传改变与基因改变有一个重要的区别就是表观遗传改变是可逆的,通过使用相应的表观遗传药物可使沉默的抑癌基因重新表达。骨髓增生异常综合征（MDS）的表观遗传治疗已经取得了很大的发展,当前应用于临床的表观遗传药物主要包括DNA去甲基化药物和去乙酰化酶抑制剂。得到FDA批准上市的DNA去甲基化药物5-氮杂胞苷和地西他滨均为MDS治疗药物,可作为中高危患者尤其是不能耐受化疗的老年患者重要的治疗选择;去乙酰化酶抑制剂如丙戊酸等目前在治疗MDS中大多处于I期临床试验阶段,可能在治疗低危MDS中有一定价值,但其剂量和治疗效果尚需进一步评估;去甲基化药物和去乙酰化抑制剂二者联用治疗MDS可能具有协同作用,但目前的临床试验尚不能证实其优于去甲基化药物的单用,仍需大样本的临床病例和合理的治疗方案来验证其安全有效性。     

骨髓增生异常综合征相关基因突变的研究进展

骨髓增生异常综合征（MDS）是一组骨髓造血干细胞恶性克隆性疾病。随着分子生物学技术在科学研究和临床实践中的广泛应用,已有研究表明基因突变是 MDS 发生及进展的重要原因,MDS 临床异质性大小与基因突变的多样性密切相关,基因研究在 MDS 诊断、分型和预后判断中将发挥越来越重要的作用。文章对近年来 MDS 常见基因突变的研究进展进行综述。     

骨髓增生异常综合征原癌基因Bmi-1表达的检测

目的：检测原癌基因Bmil在骨髓增生异常综合征（myelodysplastic syndrome,MDS）患者中的表达,探讨其在MDS中的临床意义。方法：选择201009—04—2013—01-10在泰山医学院附属医院就诊的69例MDS患者及30例非恶性血液病患者骨髓标本,应用SYBRGreen相对定量RT—PCR方法,进行Bmi-1基因的检测。结果：Bmi—1基因在非恶性血液病患者中无表达。在69倒MDS患者中均有表达（2．28±0．84）,且表达水平明显高于非恶性血液病患者组,t=14．787,P〈0．001。其中,RA组明显高于对照组（P〈0．001）,RAEB组明显高于RA组,P=0．001。Bmil基因高表达组CD34＋CD38-CD123＋／CD34＋为（10．77±5．51）％,低表达组为（4．65±3．36）％,差异有统计学意义,t=5．741,P=0．037。Bmi-1基因高表达组,骨髓原始细胞≥5％的病例数（17例）高于低表达组（14例）,χ2=7．057,P=0．012;Bmi1基因高表达组具有预后不良染色体核型的有6例,Bmi-1低表达组仅有3例,但两组间差异无统计学意义,χ2=2．794,P=0．144。结论：MDS患者的骨髓单个核细胞中均存在Bmi-1基因不同程度的表达升高,为MDS的诊断及预后的评价提供了新的方向。     

RUNX1基因突变在骨髓增生异常综合征中的研究进展

骨髓增生异常综合征(MDS)是一组起源于造血干细胞的异质性克隆性疾病。近年来随着高通量测序技术的发展, 在MDS中发现了多种类型基因突变。在与转录相关基因中, RUNX1基因突变发生率较高。RUNX1是转录核心结合因子家族的成员, 是正常造血过程的关键调节因子。RUNX1突变可导致转录活性下降以及与DNA结合障碍。近年来研究表明, RUNX1突变是MDS预后不良的独立危险因子, 伴有RUNX1突变的MDS患者可能有更高的白血病转化风险以及较短的总生存期。文章就伴RUNX1突变MDS患者的发病机制、临床特点、治疗等方面进行综述。     

骨髓增生异常综合征的治疗进展

骨髓增生异常综合征是一组造血干细胞克隆性疾病,因病态造血导致进行性、难治性血细胞减少为特征,临床主要表现为贫血、感染和出血。少数有进展为急性白血病的危险。目前仍缺乏有效的根治疗法,本文重点讨论MDS的现有治疗和相关的支持治疗。     

Prognostic value of ASXL1 mutations in patients with myelodysplastic syndromes and acute myeloid leukemia: A meta-analysis

Additional sex combs-like 1 (ASXL1) mutations, a hotspot in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have been frequently reported for their potential prognostic value, but the results are controversial. Therefore, a meta-analysis was performed. Databases, including PubMed, Embase, and Cochrane Library, were searched for relevant studies published up to January 13, 2022. STATA v16.0 software was used to calculate the combined hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and AML transformation. Subgroup analysis was used to explore the effects of the grouping factors on heterogeneity.Ten studies on ASXL1 mutations and the prognosis of MDS were selected. Our results indicate that ASXL1 mutations have an adverse prognostic impact on OS (HR = 1.68,95%CI:1.45–1.94, p < .0001) and AML transformation (HR = 2.20,95% CI:1.68–2.87, p < .0001). The results for different age groups were not significantly different (HR = 1.87,95% CI: 1.31–2.67; HR = 1.62,95% CI:1.35–2.07). Ten studies covering 5816 patients with AML were included. The pooled HR for OS was 1.37 (95% CI:1.20–1.56, p < .0001). ASXL1 mutations were especially associated with a poorer OS in the subgroup aged ≥60 years (HR = 2.86, 95% CI:1.34–6.08, p = .006); when considering cytogenetically normal AML (CN-AML), the HR was 1.78(95% CI:1.27–2.49, p = .001). This meta-analysis indicates an independent, adverse prognostic impact of ASXL1 mutations in patients with MDS and AML, which also applies to patients with CN-AML. Age was a risk factor for patients with AML and ASXL1 mutations but not for patients with MDS.     

High Frequency of ASXL1 and IDH Mutations in Young Acute Myeloid Leukemia Egyptian Patients

Background: Prognostication of AML patients depends on association of genetic and epigenetic abnormalities. We aimed to evaluate the frequency and prognostic significance of Additional Sex comb’s Like1 (ASXL1), Isocitrate Dehydrogenase (IDH) and Casitas B- lineage Lymphoma (CBL) mutations in AML assessing their association with different cytogenetic risk category. Methods: We used High Resolution Melting (HRM) technology that detects small differences in PCR amplified sequences by direct melting using EvaGreen saturating dye to analyze epigenetic mutations in 70 denovo AML patients. Results: Median age of AML patients was 39.5 years (18-75). ASXL1, IDH and CBL mutations were detected in 14 (20%), 10 (14%) and 5 (7%) patients, respectively. Mean age of ASXL1 and IDH mutants vs. wild type was 35.9±14.6 years and 42.9±14.4 years (p=0.114) and 46.7±15.2 years vs. 40.6±14.5 years (p=0.290), respectively. AML cytogenetic risk groups included low (25/70, 36%), intermediate (33/70, 47%) and high-risk (12/70, 17%). Nine/14 (64%) ASXL1 and 8/10 (80%) IDH mutants were classified as intermediate risk and 9 ASXL1 positive (64%) were adolescent and young adults (AYA). Overall survival (OS) of mutant ASXL1 vs. wild type was 1.1 years (95% CI 0.83-1.4) vs. 1.9 years (95% CI 0.71-7.51), respectively (p=0.056). OS of mutant IDH vs. wild type was 1.25 years (95% CI 0.85-1.6) vs. 1.8 years (95% CI 1.2-6.7), respectively (p=0.020). In intermediate risk cytogenetic group, ASXL1 and IDH mutants had shorter OS than wild type; 1.1 years (95% CI 0.97-1.2) vs. 2.1 years (95% CI 0.14-10.8) (p=0.002) and 1.8 years (95% CI 0.69-3.15) vs. 2.3 years (95% CI 1.1-5.5) (p=0.05), respectively. Conclusion: ASXL1 and IDH mutations occur at a high incidence among young Egyptian AML patients with intermediate risk cytogenetics and confer a poorer outcome. Integration of mutations into risk profiling may predict outcome and impact therapeutic approach of young AML patient with uncertain prognosis.     

Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.     

Treatment of myelodysplastic syndromes

The IPSS scoring system is useful to establish the appropriate treatment plan in MDS. Growth factors may alleviate both anemia and neutropenia in some MDS patients. Serum Epo levels and need for transfusion serve as good predictors of the erythroid response to the combination of Epo and G-CSF. Subgroups of MDS patients may respond favorably to immunosuppressive therapies such as CyA and ATG. Low-dose chemotherapy may also improve peripheral blood counts. Platelet counts, bone marrow cellularity, chromosome aberrations, and ringed sideroblasts combine to create a model predicting the response to low-dose ara-C. High-dose chemotherapy may lead to complete remission in about half of MDS patients, but the duration of remission is often short. The only proven curative therapy for MDS is allogeneic stem cell transplantation, resulting in an overall disease-free survival rate of about 40%. Only a minority of patients, however, can undergo allogeneic transplantation, both because of patient age and the availability of suitable donors. Autologous stem cell transplantation may be an option for selected patients who are unable to find allogeneic donors. Because the clinical features of patients with MDS are quite heterogeneous, the development of more accurate predictive models may be necessary to improve the efficacy of treatment.     

骨髓增生异常综合征发病分子机制研究进展

骨髓增生异常综合征(MDS)发病相关基因已经成为国内外的研究热点.MDS中最常见的基因突变有表观遗传调节子突变(TET2、ASXL1、DNMT3A)、RNA剪接子突变(SF3B1、SRSF2、U2AF1、ZRSR2)、信号转导调节因子突变(NRAS、JAK2)和转录因子突变(RUNX1、TP53)等.已证实基因突变在MDS发病分子机制中起着决定性的作用,并且与某些临床表型、疗效及预后密切相关,深入研究MDS分子发病相关基因,对于明确MDS的发病机制,寻找治疗靶点具有重要意义.     

骨髓增生异常综合征各亚型染色体核型分布与预后的关系

目的 探讨骨髓增生异常综合征（MDS）各亚型中的染色体核型分布特点及其与预后的关系。方法 回顾分析151例原发性MDS患者的染色体核型,比较各亚型中的染色体核型分布特点、国际预后积分系统（IPSS）评分、白血病转化率及死亡率等,并比较其在汉族与维吾尔族MDS患者中有无民族差异性。结果 所有患者核型异常检出率为55.0 %（83／151）,其中简单异常占53.0 %（44／83）,复杂异常占47.0 %（39／83）。伴多系病态造血的难治性血细胞减少症（RCMD）、原始细胞过多的难治性贫血（RAEB）-Ⅰ、RAEB-Ⅱ亚型中复杂异常的检出率明显高于难治性贫血（RA）、环形铁粒幼细胞增多的RA（RARS）亚型。核型异常涉及各条染色体,发生频率较高的染色体畸变依次为-5／5q-、-7／7q-、＋8、-20／20q-、-X／-Y、i（17q）、9p-／9q-、＋21等。IPSS评分在各亚型中差异有统计学意义（χ2＝117.802,P＜0.01）;高危组的核型异常检出率明显高于低危组和中危组（均P＜0.05）。随访151例患者白血病转化率和死亡率分别为25.2 %（38／151）和43.7 %（66／151）,核型异常者白血病转化率和死亡率明显高于核型正常者（均P＜0.05）。核型异常者白血病转化中位时间和生存中位时间均短于核型正常者。汉族与维吾尔族MDS患者各亚型分布、核型异常特点及白血病转化率、死亡率等方面差异均无统计学意义（均P＞0.05）。结论 染色体核型异常在MDS不同亚型中存在差异且与预后密切相关,是影响MDS患者病情进展及预后的重要指标,对MDS的正确诊断、病情监测及预后评估有重要意义。     

WT1基因在骨髓增生异常综合征患者中的表达

 目的　探讨WT1基因在骨髓增生异常综合征（MDS）诊断和预后判断中的意义。方法　采用骨髓涂片提取RNA,通过荧光定量RT-PCR方法,检测45例MDS患者及10例健康人骨髓涂片中WT1表达水平。结果　MDS各亚型WT1基因表达与健康对照组差异有统计学意义,与MDS患者的疾病进展呈正相关;半年内发展为难治性贫血伴原始细胞过多（RAEB）／转化中的难治性贫血伴原始细胞过多（RAEBt）的难治性贫血（RA）患者,其 WT1表达明显高于半年内病情稳定的RA患者;在RA期间,WT1表达水平的波动小于1个对数级,从RA发展到RAEB时,WT1表达水平增长1个对数级以上。结论　WT1基因可作为MDS疾病进程的标志物;若WT1表达水平比健康对照平均值高2个对数级,提示可能诊断为RA;若RA患者的WT1表达水平上升大于1个对数级,提示MDS近期内可能发生疾病进展。