骨髓增生异常综合征45例患者的染色体核型研究

目的:探讨骨髓增生异常综合征(MDS)患者染色体异常克隆与WHO分型及临床转归的关系。方法:采用骨髓短期培养和G显带技术对45例MDS患者进行染色体核型分析,同时追踪其临床病情进展情况。结果:45例MDS患者中有27例(60%)检出异常克隆。在异常染色体核型中 8和高度复杂异常最多,其次为-7/7q-和复杂异常。难治性贫血(RA)异常核型检出率33.3%,难治性血细胞减少伴多系增生异常(RCMD)异常核型检出率66.6%,难治性贫血伴原始细胞增多(RAEB)异常核型检出率75%。45例患者经追踪观察,16例(35.5%)患者转化为急性白血病,其中复杂和高度复杂核型异常7例,3例 8患者,2例-7/7q-患者,4例在初诊时核型正常。国际预后评分系统(IPSS)评分中低危组和中危1组白血病转化率为0,中危2组白血病转化率为18.2%,高危组为70%,明显高于其他3组,差异有统计学意义。结论:染色体核型分析在MDS的预后评估中有重要价值。     

老年骨髓增生异常综合征患者染色体核型及临床研究

目的探讨骨髓增生异常综合征（MDS）患者染色体异常克隆与WHO分型及临床转归的关系，以及老年MDS患者国际预后积分系统（IPSS）分组特点。方法采用骨髓短期培养和G显带技术对48例MDS患者进行染色体核型分析，同时追踪其临床病情进展情况。结果48例MDS患者中，老年患者28例，占58．3％。IPSS评分中危2组和高危组老年患者为21例，占75％，非老年患者11例，占55％。在48例患者中有28例检出异常克隆，以高度复杂异常和＋8最多。难治性贫血（RA）异常核型检出率29．4％，难治性血细胞减少伴多系增生异常（RCMD）异常核型检出率66．6％，难治性贫血伴原始细胞增多（RAEB）异常核型检出率76％。48例患者经追踪观察，17例（11例为老年患者）转化为急性白血病，其中复杂和高度复杂核型异常者8例。IPSS评分中高危组白血病转化率为71．4％，明显高于其它组。结论老年MDS患者中，中高危患者比例高，染色体核型分析在MDS的预后评估中有重要价值。     

荧光原位杂交与染色体核型分析对骨髓增生异常综合征的诊断作用

目的探讨荧光原位杂交与染色体核型分析在骨髓增生异常综合征(MDS)的应用价值,为MDS染色体异常检查提供指导。方法 78例MDS患者分别进行染色体核型分析和荧光原位杂交检查,比较两种检测方法染色体异常检出率及国际预后分期系统评分差异。结果染色体核型分析检测出染色体异常34例(43.59%),分别为+8异常14例,-7/7q-异常7例,-20/20q-异常5例,-5/5q-异常4例,Y染色体异常3例,+9异常2例,+3异常2例,-15异常2例,t(1)/1q-异位2例,-18异常1例,13例标本因分裂象不足未能成功进行核型分析。荧光原位杂交检测出染色体异常41例(52.56%),包括+8异常21例,-7/7q-异常11例,-20/20q-异常6例,-5/5q-异常4例,Y染色体异常4例。两种检测方法染色体异常检出率的差异无统计学意义(P0.05)。两种检测方法的国际预后分期系统评分差异无统计学意义(P0.05)。结论染色体核型分析仍是目前判定MDS患者染色体异常的基础方法,荧光原位杂交能够提高特定染色体异常检出率,两者联合应用更有利于染色体异常的鉴定。     

骨髓增生异常综合征进展为急性髓性白血病伴染色体核型由三体8向四体8演变1例报告并文献复习

目的通过报告1例骨髓增生异常综合征(MDS)患者在疾病进展过程中染色体核型由8号染色体三体型(三体8)向8号染色体四体型(四体8)演变的病例,结合文献复习,提高对MDS疾病进展过程中染色体核型演变及四体8异常克隆的认识.方法针对此例患者进行了病例分析及文献复习.结果该例患者在确诊MDS-伴原始细胞增多的难治性贫血(RAEB)后35个月进展为急性髓性白血病(AML)-M5,同时染色体核型由三体8向四体8演变;向AML转化后患者对化疗耐药,短期内死亡.结论染色体核型演变与MDS病情进展密切相关,四体8克隆由三体8演变而来,四体8的出现与MDS向急性白血病转化有关,是预后不良的因素.     

急性红白血病55例染色体特征和预后分析

目的探讨急性红白血病（M6）染色体特征和预后因素。方法回顾性分析55例患者染色体核型特征,采用病例对照方法,分为原发组和骨髓增生异常综合征（MDS）转化组;染色体核型异常组和正常组,并分析各组异基因造血干细胞移植（all-HSCT）治疗和（或）化疗疗效及生存预后因素。结果45例经染色体检查,18例正常,染色体异常检出率为60．0％（27／45）,其中复杂异常17例,简单异常10例,10例可见亚二倍体或超二倍体明显增多,18．5％（5／27）5号染色体受累,25．9％（7／27）7号或8号染色体受累。55例患者完全缓解（CR）率63．6％;MDS转化组CR率（42．8％）显著低于原发组（85．2％）,P〈0．05;染色体核型异常组CR率（37．0％）显著低于正常组（83．3％）,P〈0．01。生存预后因素：随访中位时间30（3—79）个月,染色体核型异常组和MDS转化M6患者生存期（OS）和无病生存期（DFS）,移植治疗者较化疗者显著延长（P〈0．01）。16例患者行all-HSCT治疗,其中9例为染色体核型异常MDS转化M6患者,4例为未缓解患者;移植后11例DFS 28个月,2年生存率68．7％（11／16）。结论染色体核型异常和（或）MDS转化M6患者常规化疗疗效差、生存期短,预后差,all-HSCT治疗显著延长生存期,改善预后,染色体核型异常和（或）MDS转化M6患者,宜早期all-HSCT治疗。     

单纯+8染色体改变的骨髓增生异常综合征24例分析

＋8染色体改变是原发性骨髓增生异常综合征（MDS）最常见的染色体核型改变之一，国外报道占原发性MDS患者10％左右，我国报道占20％～25％，居异常染色体核型改变的首位。因此，研究单纯＋8染色体改变的MDS的临床和实验室特征对于MDS的诊断和治疗以及研究其发病机制具有重要意义。我们回顾性研究24例单纯＋8染色体改变MDS的临床及实验室特征。     

骨髓增生异常综合征进展为急性髓性白血病伴染色体核型由三体8向四体8演变1例报告并文献复习

目的:通过报告1例骨髓增生异常综合征(MDS)患者在疾病进展过程中染色体核型由8号染色体三体型(三体8)向8号染色体四体型(四体8)演变的病例,结合文献复习,提高对MDS疾病进展过程中染色体核型演变及四体8异常克隆的认识。方法:针对此例患者进行了病例分析及文献复习。结果:该例患者在确诊MDS-伴原始细胞增多的难治性贫血(RAEB)后35个月进展为急性髓性白血病(AML)-M5,同时染色体核型由三体8向四体8演变;向AML转化后患者对化疗耐药,短期内死亡。结论:染色体核型演变与MDS病情进展密切相关,四体8克隆由三体8演变而来,四体8的出现与MDS向急性白血病转化有关,是预后不良的因素。     

骨髓增生异常综合征中的亚急性髓性白血病临床与细胞遗传学研究

目的从临床和细胞遗传学的角度分析骨髓增生异常综合征(MDS)中部分病例是否可更早的诊断为白血病,并探讨亚急性髓性白血病(Sub-AML)作为白血病一种类型的可能性。方法应用骨髓细胞短期培养法和染色体G显带技术,部分病例联合应用荧光原位杂交技术(FISH),对42例细胞遗传学检查具有 8异常克隆,16例具有-7／7q-异常克隆,以及55例虽然经常规细胞遗传学检查未检出异常克隆,但是骨髓涂片原始细胞≥0．10,按照FAB或WHO标准既往诊断为MDS的病例进行了临床及血液形态学和细胞遗传学的系列研究。结果在同期173例有异常克隆的患者中, 8患者最多42．8％(74例),其次-7／7q-为15．0％(26例);42例 8患者中位原始细胞计数0．08,在18个月的中位随访时间内,40．0％(12例)的患者进展为显著的白血病(FL),总的中位生存时间为20个月;16例-7／7q-患者中位原始细胞计数0．135,在20个月的中位随访时间内,43．8％(7例)的患者进展为FL,总的中位生存时间仅10个月;55例核型正常的患者,骨髓中位原始细胞为0．148,52．7％(16例)的患者进展为FL,总的中位生存时间为34个月。结论 8和-7／7q-的患者均有恶性的白血病细胞克隆存在,亚急性而进行性的疾病经过表明宜归人Sub-AML。对于细胞遗传学检查为正常核型,但骨髓中原始细胞≥0．10的患者,应严密随访,他们中的部分患者实际也可能是早期Sub—AML。     

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。     

21例骨髓增生异常综合征患者的染色体核型分析

骨髓增生异常综合征（MDS）系克隆性造血干细胞疾病，临床以无效造血和外周血细胞减少为特征，约50％患者有染色体异常。2003-2004年，我们对21例MDS患者的染色体核型进行了分析，旨在探讨染色体核型对MDS诊断、鉴别和预后判断的价值。     

A single-center population-based consecutive series of 1500 cytogenetically investigated adult hematological malignancies: karyotypic features in relation to morphology, age and gender

During the 18-yr period 1976-93, a population-based series of 1586 adults with suspected or confirmed hematological malignancies were successfully cytogenetically investigated at a single center. Eighty-six cases were excluded due to unretrievable medical records or if analyzed only in remission or at relapse. The remaining 1500 medical records were reviewed regarding morphology and clinical parameters in order to investigate possible associations between karyotypic pattern (normal, 1, 2 or complex anomalies; specific abnormalities) and gender, age and morphological subgroups. The impact of time-period, i.e. 1976-87 vs. 1988-93, and referring center on cytogenetic findings was also studied. A total of 372 acute myeloid leukemias (AML), 389 myelodysplastic syndromes (MDS), 64 acute lymphoblastic leukemias (ALL) and 262 chronic myeloid leukemias (CML) were identified, altogether 1087 cases. Patients with other (n=261) or no hematological malignancies (n = 152) were excluded from the present analysis. Cytogenetic abnormalities were detected in 52% AML, 51 % MDS, 68% ALL and 97% CML, frequencies that did not differ significantly between the 2 time periods or referring centers. No significant age- or gender-related differences in karyotypic patterns were discerned in AML, MDS, ALL or CML, whereas the karyotypic patterns varied among the FAB groups in both AML (p= 0.001) and MDS (p < 0.001). The specific abnormalities t(8;21), t(15;17) and inv(16) were more common (p < 0.001) in younger AML patients and 5q- was more frequent in females with MDS (p<0.001). These findings indicate, in contrast to previous series, that neoplasia-associated karyotypic aberrations are not more common among older patients or in males.     

急性髓性白血病178例患者的细胞遗传学特征

目的 探讨急性髓性白血病(AML)患者的细胞遗传学特征.方法 采用骨髓短期培养和G显带技术对178例AML患者进行染色体核型分析.结果 178例患者中,171例有足够可供分析的中期分裂象.171例患者异常克隆检出率74.9%.其中27例患者为骨髓增生异常综合征(MDS)继发AML,其异常克隆榆出率为92.6%,在其余144例原发AML中异常克隆检出率为71.5%,MDS继发AML异常克隆检出率明显高于原发AML患者.171例患者中预后良好核型占24.0%,预后中等核型占46.8%,预后不良核型占29.2%.在预后良好核型中以t(15;17)为多;在预后中等核型中以正常核型为主;在预后不良核型中以复杂异常核型为主,复杂核型的异常克隆中常含有-5/5q-、-7/7q-等具有不良预后的异常克隆.老年组75例患者中,预后良好、预后中等及预后不良核型分别为16.0%、48.0%及36.O%,年轻组96例患者中分别为30.2%、45.8%及24.0%.老年患者预后良好核型比例低于年轻患者.MDS继发AML患者预后不良核型比例及单体核型比例均高于原发AML患者(P值均<0.001).结论 t(15;17)、正常核型、复杂核型分别是AML最常见的预后良好核型、预后巾等核型及预后不良核型.MDS继发的AML及老年AML患者染色体核型预后不良.

Abstract：

Objective To explore the cytogenetic characteristics of acute myeloid leukemia(AML) patients.Methods The karyotype analysis was performed in 178 AML using the short-term culture of bone marrow cell and G-banding technique.Results Among the 178 patients,171 had enough metaphases for analysis and 128(74.9%)had clonal karyotypic abnormalities.Twenty-seven patients were secondary to myelodysplastic syndrome (MDS-AML),with 25 (92.6%) patients carrying clonal karyotypic abnormalities.Among the remaining 144 patients of de novo AML,103(71.5%)had clonal karyotypic abnormalities.The rate of abnormal clonal karyotype was higher in MDS-AML than that of de novo AML (P=0.021).Among the 171 patients,41(24.0%)were in favorable risk group,80(46.8%)in intermediate risk group and 50(29.2%)in adverse risk group.t(15;17)was the most common chromosomal aberration.The maiority intermediate risk chromosomal aberration was;normal karyotype.The most common cytogenetic abnormality among adverse group was a complex karyotype.Adverse cytogenetic aberrations,such as -5/5q-,-7/7q-,frequently occurred in conjunction with one another as part of a complex karyotype.Totally 75 patients were 60 years or older,among them,16.0%were in favorable risk group,48.0%in intermediate risk group and 36.0%in adverse risk group.Among 96 younger patients,30.2%were in favorable risk group.45.8%in intermediate risk group and 24.0%in adverse risk group.The rate of favorable risk chromosomal aberration was lower in elder patients than in younger(P=0.03 1).The rate of adverse risk chromosomal aberration and the rate of monosomal karyotype were higher in MDSAML than in de novo AML patients(P<0.001).Conclusions The most common favorable,intermediate and adverse chromosomal aberrations were t(15;17),normal karyotype and complex karyotype respectively.The karyotype was poor in MDS-AML and elder AML patients.     

Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia

Development of myelodysplasia (MDS) with subsequent progression to acute myeloid leukemia (AML) is an example of the multistep process of malignant transformation in which each step often relates to genetic abnormalities that can be directly seen as chromosomal aberrations. Therapy-related MDS and AML (t-MDS and t-AML) may serve as an ideal model for a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is often diagnosed early due to a close patient follow-up. The cytogenetic characteristics at diagnosis were studied in 137 consecutive cases of t-MDS and t-AML, including 22 new cases, and correlated with the clinical characteristics and the course of the disease. Balanced translocations to chromosome bands 11q23 and 21q22 represent primary steps in pathways leading directly to overt t-AML. Specific chromosomal deletions or losses, on the other hand, represent primary or secondary events in alternative pathways leading to t-MDS with potential for subsequent transformation to overt t-AML. Loss of a whole chromosome 7 (-7) or deletion of its long arm (7q-) and deletion of the long arm of a chromosome 5 (5q-) were the most frequent primary abnormalities significantly related to t-MDS. Loss of a whole chromosome 5 (-5) was also a primary event, but surprisingly, was observed equally in t-MDS and in t-AML. Deletion of chromosome 13, including bands q13q14, was another less common primary aberration of t- MDS. Except for -7 and del(13q), these primary aberrations were most often observed together with secondary abnormalities. These included balanced aberrations involving band 3q26 and various deletions of chromosome 3, a gain of a whole chromosome 8, deletions of the short arm or loss of chromosomes 12 and 17, loss of a whole chromosome 18, and deletions of the short arm of chromosome 21. Deletions or loss or chromosomes 5 and 7 were significantly associated with previous therapy with alkylating agents (P = .002), and balanced translocations to chromosome bands 3q26, 11q23, and 21q22 were significantly associated with previous therapy with drugs targeting DNA-topoisomerase II (P < .00005). Other characteristic aberrations were not related to any specific type of therapy. The molecular changes believed to contribute to the development of t-MDS and t-AML have been identified for many of these chromosomal abnormalities.     

Sole abnormalities of chromosome 7 in myeloid malignancies: spectrum, histopathologic correlates, and prognostic implications

Among 6,565 consecutive abnormal cytogenetic reports at our institution, 3,192 (49%) constituted sole abnormalities, of which 230 (7%) involved chromosome 7: monosomy 7 (n = 98), 7q- (n = 51), der(1;7)(q10;p10) (n = 44), balanced translocations (n = 15), ring 7 (n = 13), and 7p- (n = 9). The most frequent histopathologic correlates were myelodysplastic syndromes (MDS; 28%), acute myeloid leukemia (AML; 17%), secondary or therapy-related MDS/AML (13%), primary myelofibrosis (PMF; 7%), and chronic myelomonocytic leukemia (6%). Monosomy 7 was the most frequent in each one of these disease categories except PMF where 7q- was more frequent. In primary MDS, patients with der(1;7)(q10;p10) (n = 13), compared to those with monosomy 7 (n = 30) or 7q- (n = 15), were less likely (P = 0.04) to display excess blasts or multilineage dysplasia but overall and leukemia-free survival adjusted for these variables revealed no significant difference between the three groups (P = 0.57 and 0.81, respectively). The current study does not prognostically distinguish monosomy 7 from 7q- or der(1;7), in MDS.     

Design and validation of DNA probe sets for a comprehensive interphase cytogenetic analysis of acute myeloid leukemia

The objective of this study was to design DNA probe sets that enable the detection of chromosome aberrations in acute myeloid leukemia (AML) by interphase cytogenetics using fluorescence in situ hybridization (FISH) and to compare the results of interphase cytogenetics with those of conventional chromosome banding analysis. One hundred five consecutive patients with adult AML entered on a multicenter treatment trial were studied with a comprehensive set of DNA probes recognizing the most relevant AML-associated structural and numerical chromosome aberrations: translocations t(8;21), t(15;17), and t(11q23); inversion inv(16);chromosomal deletions (5q-, 7q-, 9q-, 12p-, 13q-, 17p-, and 20q- ); and chromosomal aneuploidies. Interphase cytogenetics was particularly sensitive for detecting the AML-specific gene fusions: 3 additional cases of inv(16) and 1 additional case of t(8;21) were identified by FISH that were missed by banding analysis, whereas equal numbers of t(11q23) and t(15;17) were detected. Five additional cases of trisomy 8q, 3 more cases of trisomy 11q, and 2 more cases of trisomies 21q and 22q were shown by FISH. These aberrations were either masked in complex karyo-types or identified in cases in which conventional banding analysis failed. On the other hand, the DNA probes selected were not informative to detect 1 case of 5q-, 9q-, and 20q-. In 5 cases, clonal aberrations were detected on banding analysis for which no FISH probes were selected. In conclusion, interphase cytogenetics proved to be more sensitive for detecting AML-specific chimeric gene fusions and some partial trisomies. Interphase cytogenetics provides a powerful technique complementary and, with further development of diagnostic DNA probes, even an alternative to chromosome banding studies for the cytogenetic analysis of AML.     

Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia

A serious complication of aplastic anemia (AA) is its evolution to clonal hematologic diseases such as myelodysplasia (MDS) and leukemia, which is usually associated with the appearance of a cytogenetic abnormality in bone marrow cells. We present here an analysis of a cohort of 30 patients with otherwise typical AA in whom clonal karyotypic evolution was observed during frequent periodic marrow examinations. The actuarial risk for this complication has been estimated in other studies at around 15% at 5 years. Conversion from normal to abnormal karyotype occurred at a constant rate after initial diagnosis, with about 50% of cases developing within the first 30 months. Transient chromosomal abnormalities were infrequent. Clinically, AA patients with clonal cytogenetic patterns were heterogenous; a variety of karyotypic defects with numerical and structural abnormalities of chromosome 7 accounted for 40% of all cases followed by trisomy 8, structural and numerical abnormalities of chromosome 13, deletion of Y chromosome, and complex cytogenetic abnormalities. Unlike in primary MDS, aberrancies of chromosome 5 and 20 were infrequent. The clinical course depended on the specific abnormal cytogenetic pattern. Most deaths related to leukemic transformation occurred in patients with abnormalities of chromosome 7 or complex cytogenetic alterations or both. Evolution of chromosome 7 abnormalities was seen most often in refractory patients who had failed to respond to therapy. In contrast, trisomy 8 developed in patients with good hematologic responses who often required chronic immunosuppression with cyclosporine A (CsA), and survival was excellent. Although AA patients with monosomy 7 showed a similar prognosis to those with primary MDS, trisomy 8 in AA appears to have a more favorable prognosis than in MDS.     

Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia

OBJECTIVE: Bone marrow mesenchymal stroma cells (BMSC) are key components of the hematopoietic microenvironment. The question of whether BMSC from patients with hematological disorders have cytogenetic abnormalities is discussed controversially, some studies indicating that they are cytogenetically normal and others providing evidence of their aberrations. PATIENTS AND METHODS: We performed standard and molecular cytogenetic analyses of both hematopoietic cells and BMSC from 31 patients with myelodysplastic syndrome (MDS, n = 18) and acute myeloid leukemia (AML, n = 13) and 7 healthy individuals. Mononuclear cells were isolated from fresh bone marrow aspirates at the time of initial diagnosis for cytogenetic analysis of hematopoietic cells (HC) and selection of BMSC. RESULTS: Clonal cytogenetic aberrations were observed in HC from 8 (44%) MDS and 8 (61%) AML patients. Cytogenetic analyses of BMSC were successfully performed in 27 of the 31 cases. Structural chromosomal aberrations, including t(1;7), t(4;7), t(7;9), t(7;10), t(7;19), t(15;17), and others, were detectable in BMSC from 7 of 16 (44%) MDS and 6 of 11 (54%) AML patients. The breakpoints of chromosomes in BMSC were typical for leukemia aberrations. Two patients showed clonal chromosomal markers. CONCLUSIONS: BMSC from MDS and AML patients show chromosomal abnormalities. Although the majority of cytogenetic aberrations in BMSC were not clonal and differed from chromosomal markers in HC from the same individual, detection of typical chromosomal changes in BMSC suggests enhanced genetic susceptibility of these cells in MDS/AML. This may indicate potential involvement of BMSC in the pathophysiology of MDS/AML.     

The prognostic significance of cytogenetic aberrations in childhood acute myeloid leukaemia. A study of the Swiss Paediatric Oncology Group (SPOG)

In childhood-onset acute myeloid leukaemia (AML) the clinical value of karyotypic aberrations is now acknowledged, although there is still debate concerning the prognostic significance of some events. To add to this knowledge, cytogenetic analysis was performed on a consecutive series of 84 childhood AML patients diagnosed in Switzerland. A result was obtained for all patients, with 69 (82%) showing a clonal karyotypic aberration. In the remaining 15 (18%), no karyotypic aberration was seen by either conventional or fluorescence in situ hybridisation analyses. The most frequent aberrations observed were t(11q23) (19% of all patients), t(8;21) (12%) and +8 (11%). Except for cytogenetics, no clinical parameter was shown to be significantly associated with outcome. The analysis of individual cytogenetic subgroups demonstrated that aberrations involving chromosome 16q were the strongest predictor of a good prognosis, while +8 and complex karyotypes represented the strongest predictors of a poor prognosis. It was also noteworthy that patients with the rare aberrations of del(11q) (n = 4) and t(16;21)(p11;q22) (n = 3) had a poor outcome. The results support the importance of cytogenetic analysis in childhood AML, but show that further work is required in the classification of the poor prognosis aberrations.