骨髓增生异常综合征的遗传学研究进展

骨髓增生异常综合征(MDS)是起源于造血干细胞的恶性克隆性疾病,包括一组以骨髓无效造血、病态造血改变、克隆性染色体异常和高风险向急性髓性白血病(AML)转化的临床表现高度异质性疾病。目前认为,MDS临床表现的异质性很可能是由于基因不稳定性引起的,这种基因不稳定性主要表现在细胞遗传学异常、基因突变以及表观遗传学异常等〔1-2〕。随着遗传学技术的更新,近几年     

骨髓增生异常综合征的临床与细胞遗传学研究

我们对近年来收治的30例骨髓增生异常综合征(MDS)患者进行了细胞形态学，细胞遗传学和有关临床资料分析，旨在探讨MDS的细胞遗传学、血液学与预后的相互关系。     

骨髓增生异常综合征435例WHO分型和细胞遗传学分析

目的 探讨我国骨髓增生异常综合征(MDS)WHO亚型分布和细胞遗传学异常特点,并与西方国家进行比较.方法 采用前瞻性方法收集了协作组435例MDS患者,进行WHO分型,采用染色体G显带和荧光原位杂交(FISH)技术进行细胞遗传学分析.结果 MDS中位发病年龄为58(18～90)岁.难治性血细胞减少伴多系发育异常(RCMD)病例比例最高,约占69.6%(303/435),其他亚型依次为难治性贫血伴原始细胞增多(RAEB)24.1%(105/435)、难治性贫血(RA)2.3%(10/435)、不能分类MDS(MDS-U)2.3%(10/435)、难治性贫血伴环状铁粒幼细胞增多(RAS)1.2%(5/435)和5q-综合征0.5%(2/435),而西方国家RA、RAS、5q-综合征比例较高,RCMD亚型比例低于中国.11例染色体检查失败,424例染色体检查成功的染色体克隆性异常率为38.7%(164/424),其中RAEB-Ⅰ异常率最高62.5%(25/40),其次RAEB-Ⅱ 48.4%(30/62)、RCMD 34.5%(102/296).常见的染色体异常依次为:+8为12.7%(54/424)、复杂核型为9.O%(38/424)、染色体易位为7.8%(33/424)、-20q为6.6%(28/424)、-7/-7q为5.2%(22/424)、-5/-5q为4.2%(18/424),而国外最常见的是-5/-5q、-7/-7q、+8、11q及12p/12q异常.以国际预后积分系统染色体预后分组,染色体预后良好组68.2%(289/424),预后中等组19.1%(81/424),预后不良组12.7%(54/424).有17例患者因为异常细胞的比例偏低,染色体检查正常,但FISH检测到低水平的异常.结论 我国MDS的WHO亚型分布与染色体异常分布与西方国家不同.FISH和常规染色体检查相结合,可以提高检测的灵敏度.     

去甲基化药物治疗骨髓增生异常综合征的最新进展

骨髓增生异常综合征是一组异质性很强的造血干细胞的克隆性疾病。近年来随着表观遗传学概念和理论的建立,越来越多的证据表明表观遗传学的改变可能在MDS发生发展中起到重要作用。基因的表观遗传学异常可通过抑制DNA甲基转移酶（DNMT）恢复已沉默基因的表达,这可能是临床应用去甲基化药物治疗MDS理论依据之一。虽然目前去甲基化药物的具体作用机制尚未完全阐清,     

骨髓增生异常综合征MIC异常和临床特点

目的：研究骨髓增生异常综合征（MDS）形态学、免疫学、遗传学（MIC）异常变化及临床特点.方法：对65例MDS患者的血液学、免疫学、遗传学异常改变资料进行了回顾性分析.结果：65例中外周血象全血细胞减少36例（55.4%），2系细胞减少19例（29.2%），分类可见幼红细胞35例（53.8%），幼粒细胞27例（41.5%）.贫血60例（92.3%），以中重度为主58例（89.2%），表现为大细胞或正细胞性贫血.白细胞异常56例（86.2%），以减少为主45例（69.2%）.血小板减少41例（63.1%）.65例行骨髓细胞学检查：增生活跃至极度活跃55例（84.6%），1系或1系以上病态造血54例（83.1%），11例难治性质血患者病态造血不明显（16.9%）.59例行骨髓病理学检查：3系不同程度病态造血30例（50.8%），粒系幼稚前体细胞异常定位（ALIP）29例（49.2%）.45例行骨髓细胞流式细胞仪（FCM）免疫表型测定，表现2系或2系以上异常40例（88.9%）.41例做FCM-DNA倍体分析，检出DNA非整倍体26例（63.4%）.32例做骨髓细胞染色体分析，发现异常克隆13例（40.6%）.结论：MDS临床表现不典型，血液学改变复杂，缺乏特异性，部分RA病态造血不明显，仅依靠形态学难以做出正确诊断，应提倡MIC分型诊断。     

骨髓增生异常综合征和再生障碍性贫血等细胞遗传学…

为了探讨骨髓细胞遗传分析在鉴别诊断骨髓增生异常综合征（ＭＤＳ）和再生障碍性贫血（ＡＡ）等不同血液病中的意义，我们联合应用骨髓细胞Ｒ－带核型分析和组妹染色单体分化（ＳＣＤ）检测，对３３４例ＭＤＳ，ＡＡ等不同血液病进行分析并随访。结果表明：（１）ＲＡ／ＡＡ，ＲＡ／ＩＴＰ和ＲＡ／ＨＡ等可疑ＲＡ即为不典型ＲＡ或异早期ＲＡ；（２）骨髓细胞从ＳＣＤ阳性转为ＳＣＤ阴性是骨髓细胞癌变过程：（３）骨髓细胞ＳＣＤ检测     

骨髓增生异常综合征和再生障碍性贫血等细胞遗传学研究

为了探讨骨髓细胞遗传学分析在鉴别诊断骨髓增生异常综合征（ＭＤＳ）和再生障碍性贫血（ＡＡ）等不同血液病中的意义，我们联合应用骨髓细胞Ｒ－带核型分析和姐妹染色单体分化（ＳＣＤ）检测，对３３４例ＭＤＳ、ＡＡ等不同血液病进行分析并随访。结果表明：（１）ＲＡ／ＡＡ、ＲＡ／ＩＴＰ和ＲＡ／ＨＡ等可疑ＲＡ即为不典型ＲＡ或早期ＲＡ；（２）骨髓细胞从ＳＣＤ阳性转为ＳＣＤ阴性是骨髓细胞癌变过程；（３）骨髓细胞ＳＣＤ检测和核型分析具有肯定的诊断和预后价值；（４）ＦＡＢ分类法同细胞遗传学技术相结合可明显地提高ＭＤＳ诊断率或确诊率；（５）ＭＤＳ核型异常检出率６４．４％，与国外（４０％～７０％）相仿。本系列ＭＤＳ常见染色体异常为＋８，２ｑ￣－，一５／５ｑ￣－，一７／７ｑ￣－，７ｐ￣＋，以及一１１，一１４等，也与国外相似。（６）ＭＤＳ发病最初染色体异常看来是染色体数目异常即单体性为主。     

骨髓增生异常综合征患者细胞遗传学检测临床意义

目的研究骨髓增生异常综合征患者细胞遗传学异常表型及其与MDS患者转归关系。方法采用骨髓细胞直接法或24~48小时培养法制备染色体,用RHG技术进行核型分析。结果MDS患者异常染色体出现率46%,主要有 8、-7、5q-、11q-、20q-,并有复杂异常核型。复杂异常核型患者急性白血病转化率明显高于核型正常者。结论MDS患者有异常核型者易转为急性白血病,异常染色体出现与该类患者转归有直接关系,核型分析对MDS患者预后判断有重要价值。     

骨髓增生异常综合征与免疫异常

骨髓增生异常综合征与免疫异常徐世荣骨髓增生异常综合征（ＭＤＳ）为造血干细胞疾病，不仅在细胞遗传学、分子生物学、细胞生物学、血细胞酶学等方面有异常，而且在免疫学方面也存在异常。近１０余年来，研究进一步证实免疫功能异常在ＭＤＳ发病、发展，向急性白血病（Ａ...     

Cytokine therapy for myelodysplastic syndrome

The myelodysplastic syndromes are a heterogeneous family of hematologic disorders characterized by ineffective hematopoiesis. Because of the interpatient variability regarding prognosis and morbidity, management of myelodysplastic syndromes continues to be a challenge to clinical hematologists. Pancytopenia and defective function of neutrophils and platelets carry a high risk of infectious or hemorrhagic complications. Erythropoietin is perhaps the most commonly used therapeutic option, second only to transfusion; improvement of erythropoiesis is seen in approximately 20% of patients, mainly in those with relatively preserved erythroid function and no or low transfusion requirements. Coadministration of erythropoietin with either granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor may increase the response rate up to 50%. Although prophylactic administration of granulocyte- or granulocyte-macrophage colony-stimulating factor cannot be recommended, treatment of febrile neutropenia might benefit from administration of granulocyte- or granulocyte-macrophage colony-stimulating factor in addition to antibiotics.     

Concurrent pernicious anemia and myelodysplastic syndrome

Megaloblastic anemia (MA) due to vitamin B12 deficiency is a reversible form of ineffective hematopoiesis. Myelodysplastic syndrome (MDS) is an acquired, irreversible disorder of ineffective hematopoiesis, characterized by stem cell dysfunction as a consequence of DNA damage manifested in part by karyotype anomalies. Importantly, MA and MDS are generally considered mutually exclusive diagnoses. We report the case of a 73-year-old woman with a profound macrocytic anemia, monocytosis and neurologic symptoms. Low cobalamin levels and the presence of anti-intrinsic-factor antibodies definitively established a diagnosis of pernicious anemia. Replacement therapy resulted in resolution of neurologic findings and macrocytosis; however, the anemia and monocytosis persisted. Bone marrow biopsy revealed trilineage myelodysplasia, which together with the peripheral monocytosis suggested a diagnosis of chronic myelomonocytic leukemia. Karyotype analysis revealed a clone with 45, XX, +der(1;7)(q10;p10)-7 [20]. Eighteen months after documented vitamin B12 replenishment her MDS transformed to terminal acute myeloid leukemia with the same clonal abnormality. Reversible cytogenetic abnormalities have been observed with MA, occasionally including karyotypes typically associated with MDS or myeloid leukemias. These abnormalities, like the anemia, resolve with vitamin replacement. This case suggests that MA and MDS can occur simultaneously; clinicians should be aware that this phenomenon occurs. Whether acquired karyotype abnormalities from the MA were related to the MDS and subsequent myeloid leukemia in this woman is a speculative but intriguing consideration that is discussed.     

Stem cell transplantation for aplastic anemia and myelodysplastic syndrome

Summary:Stem cell transplantation (SCT) from a histocompatible sibling is treatment of choice for severe aplastic anemia. Survival rates have been reported to be as high as 90% for children. Immunosuppressive therapy (IST) is employed in patients who are not candidates for SCT due to donor unavailability. The addition of cyclosporin A to antilymphocyte globulin has improved the response rate to 70-80%, and survival at 5 years among responders is about 90%. In all, 30% of patients treated by IST suffer from relapse, but long-term prognosis does not appear to be affected by this complication. Juvenile myelomonocytic leukemia (JMML) shares both myelodysplastic and myeloproliferative features. Survival (10-year) of patients with JMML without SCT is only 6%. Children with JMML should be transplanted early in the course of their disease. Conditioning regimen composed of three alkylating agents, busulfan, cyclophosphamide and melphalan has been favored by the EWOG-MDS and EBMT-Pediatric WP in the second half of the 1990s. SCT using this conditioning regimen is capable of curing approximately 50% of patients with JMML. More than 70% of patients with refractory cytopenia and more than 50% of children with advanced MDS are cured of by the early performed allogeneic SCT.     

Border between aplastic anemia and myelodysplastic syndrome

Distinguishing between acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS) with a low blast cell percentage is often difficult and problematic, as both diseases are syndromes primarily defined by morphological findings, and their diagnostic criteria do not necessarily reflect the pathophysiology of their bone marrow (BM) failure. As a result, many patients with benign BM failure that should be managed as AA are diagnosed as having MDS, due to the absence of BM hypocellularity and the presence of dysplastic signs in the BM, and are treated inappropriately with toxic therapies, such as hypomethylating agents, and stem cell transplantation from unrelated donors. BM failure syndromes need to be managed in ways appropriate to their pathophysiology, which is more accurately determined by using markers such as the presence of glycosylphosphatidylinositol-anchored protein-deficient cells and HLA-A lacking leukocytes. We recently found that plasma thromobopoietin level is one of the most useful markers for distinguishing benign and pre-leukemic BM failure syndromes.     

Update on the therapy for myelodysplastic syndrome

The myelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic stem cell disorders characterized by cytopenias. Patients have a risk of developing acute leukemia though most subcome to complications of low blood counts. Over the past decade many novel treatments have been developed and investigation of new agents is ongoing. In this article, we discuss the classification and prognostic systems that are used in MDS, the agents available for treatment of MDS as well as review supportive and palliative care options for patients who are not candidates for, or opt against, newer treatment strategies. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

Vitamin K2 therapy for myelodysplastic syndrome

Vitamin K2 is reported to induce apoptosis or differentiation of leukemic cell lines in vitro. We administered a vitamin K2 analog, menatetrenone, at 45 mg daily to 23 patients with myelodysplastic syndrome (MDS): 13 patients with RA, 2 with RARS, 6 with RAEB and 2 with RAEB-T. Good response (GR) and partial response (PR) were defined as an increase of hemoglobin concentration exceeding 2 g/dl and 1-2 g/dl without transfusion, respectively. Six of the RA patients showed improvement of anemia (GR, 3 patients; PR, 3 patients). RA patients who did not have a hypocellular bone marrow and were transfusion-independent tended to be responsive to vitamin K2 therapy in combination with vitamin D3 or anabolic steroids. No adverse effect of vitamin K2 was observed, and the time required to obtain the hematological response was short, being 3 months on average. We believe that vitamin K2 therapy has potential as a treatment for patients with MDS.     

Multiple responses of aplastic anemia to low-dose cyclosporine therapy despite development of a myelodysplastic syndrome

A 55-year-old white woman presented in July 1984 with severe aplastic anemia refractory to anti-thymocyte globulin, corticosteroids, and danazol. In December 1984, oral cyclosporine therapy was begun, and a partial remission was achieved with persistent thrombocytopenia and transfusion independence. The cyclosporine dosage was tapered and then stopped in May 1986 when the platelet count was 35,000/L. In October 1986 the platelet count was only 16,000/L, and the bone marrow showed evidence of a myelodysplastic syndrome; cytogenetic analysis revealed deletion of the long arm of chromosome 13 (previous cytogenetic findings had been normal). After cyclosporine therapy was resumed, platelet count promptly increased to 36,000/L. A subsequent attempt to taper the cyclosporine dosage resulted in a decreased platelet count. The platelet count responded to cyclosporine again and was maintained at 54,000/L and higher with cyclosporine therapy at only 25 mg/day. This information suggests that, despite the development of a myelodysplastic syndrome, immune mechanisms were still operative in the pathogenesis of our patient's thrombocytopenia. Immune modulation may have an important role in preventing progression of myelodysplastic syndromes to more severe forms or to acute leukemia.