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Emergence of genetic instability in children treated for leukemia

SCIENCE 2000年第5465期288卷 514-517页

作者： Finette, BA Homans, AC Albertini, RJ Univ Vermont Dept Pediat Burlington VT 05405 USA Univ Vermont Dept Microbiol & Mol Genet Burlington VT 05405 USA Univ Vermont Vermont Canc Ctr Burlington VT 05405 USA Univ Vermont Dept Med Burlington VT 05405 USA

T cells from patients who had received chemotherapy for B-lineage acute lymphocytic Leukemia were studied to determine whether genetic instability, a principal characteristic of cancer cells, can also occur in nonmalignant cells. Consistent with expectations for a genetic instability phenotype, multiple mutations were detected in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene in independently isolated mutant T cells expressing identical rearranged T cell receptor beta (TCR beta) gene hypervariable regions. These results indicate that cancer treatment can lead to genetic instability in nonmalignant cells in some individuals. They also suggest a mechanistic paradigm for the induction of second malignancies and drug resistance.

关键词：等位基因抗肿瘤药/治疗应用伯基特淋巴瘤/血液伯基特淋巴瘤/药物疗法伯基特淋巴瘤/遗传学细胞谱系细胞转化肿瘤克隆细胞抗药性肿瘤基因重排 β链T细胞抗原受体基因报告基因 T细胞受体次黄嘌呤磷酸核糖转移酶/遗传学突变肿瘤继发原发性/病因学前体细胞淋巴母细胞白血病淋巴瘤/血液前体细胞淋巴母细胞白血病淋巴瘤/药物疗法前体细胞淋巴母细胞白血病淋巴瘤/遗传学复发 T淋巴细胞青少年成年人儿童儿童学龄前人类婴儿

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Clinical significance of cytogenetic findings at diagnosis and in remission in childhood and adult acute lymphoblastic leukemia: Experience from India

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CANCER GENETICS AND CYTOGENETICS 1999年第1期110卷 44-53页

作者： Amare, P Gladstone, B Varghese, C Pai, S Advani, S Tata Mem Hosp Dept Med Oncol Cytogenet Lab Bombay 400012 Maharashtra India

We report cytogenetic findings in 114 patients of acute lymphoblastic leukemia (ALL), which includes 78 children (less than or equal to 15 years) and 36 adults (16-60 years). Chromosome aberrations;were detected in 109 (95%) cases. A lower frequency of hyperdiploidy (15%) in children and a higher frequency of hypodiploidy both in children (38.4%) and adults (44.4%) were found, in contrast to literature. Translocations were detected in one third of adult and pediatric cases. The incidence of t(9;22) was comparatively low in adults (7.7%). Frequency of t(1;19) was also low in overall ALL cases. Various other recurrent abnormalities such as del(6q), abn(11q23), i(9p), abn(12p13), del(7q), and i(17q) were seen in our cases;a striking difference in the incidence of del(6q) (41%) and abn(11q23) (30%) was found in our series versus reported literature. Ploidy distribution indicated association of pseudo;and hypodiploidy with B-lineage, and hypodiploidy with T-lineage in children-The occurrence of del(6q)) was more frequent in pediatric ALL with highly aberrant pattern and also with lymphadenopathy. Abn(11q23) was found to be early-B and pre-B specific. Kaplan-Meier analysis of overall survival revealed Prognostic value of sex, FAB, immunophenotype, and cytogenetic findings. Females and T-ALL patients had a better prognosis, whereas males and B-ALL patients had poor outcome in overall and pediatric age groups. Prognostic evaluation of cytogenetics indicated translocations as an independent high-risk predictor in childhood (P < 0.008) and adult ALL (P < 0.01). Childhood ALL with t(8;14) and t(4;11) and adults with t(9;22) had poor survival. Cytogenetics of remission marrows demonstrated disappearance of abnormal clones in 31.4%, and expansion in normal clones in 50% of patients. Persistence of original clones and development of new clones were observed in 20% and 33% of patients, respectively;whereas karyotype evolution was identified in 20% of patients. The prognostic signi

关键词：染色体畸变前体细胞淋巴母细胞白血病淋巴瘤/遗传学前体细胞淋巴母细胞白血病淋巴瘤/死亡率前体细胞淋巴母细胞白血病淋巴瘤/病理学预后存活率青少年成年人儿童儿童学龄前女(雌)性人类婴儿男(雄)性

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The "Atlas of Genetics and Cytogenetics in Oncology and Haematology" on the Internet and a review on infant leukemias

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CANCER GENETICS AND CYTOGENETICS 2000年第2期120卷 155-159页

作者： Huret, JL Dessen, P Le Minor, S Bernheim, A Univ Hosp Dept Genet Poitiers France Inst Gustave Roussy Villejuif France GIS Infobiogen Villejuif France

The "Atlas of Genetics and Cytogenetics in Oncology and Haematology" (URL: http:// ***/services/chromcancer) is a database devoted to chromosome abnormalities in cancer, cancer-prone diseases, and genes involved in cancer. The information is concise and updated. This database is made for and by cytogeneticists, molecular biologists, clinicians in oncology and hematology, and pathologists, who are encouraged to contribute. The database is herein presented, together with an example concerning congenital leukemias. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：细胞遗传学分析数据库(主题) 血液病/遗传学因特网白血病髓样急性/遗传学肿瘤/遗传学前体细胞淋巴母细胞白血病淋巴瘤/遗传学儿童学龄前人类婴儿婴儿新生

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Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第9期97卷 4790-4795页

作者： Strick, R Strissel, PL Borgers, S Smith, SL Rowley, JD Univ Chicago Dept Med Hematol Oncol Sect Chicago IL 60637 USA

Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemia. In the search for possible agents inducing infant leukemia, we identified bioflavonoids. natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines;it colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox), Both in vivo and additional in vitro experiments demonstrated topoisomerase II (topo II) as the target of bioflavonoids similar to VP16 and Dox, Based on 20 bioflavonoids tested, we identified a common structure essential for topo II-induced DNA cleavage. Reversibility experiments demonstrated a religation of the bioflavonoid as well as the VP16-induced MLL cleavage site. Our observations support a two-stage model of cellular processing of topo II inhibitors: The first and reversible stage of topo II-induced DNA cleavage results in DNA repair, but also rarely in chromosome translocations;whereas the second, nonreversible stage leads to cell death because of an accumulation of DNA damage. These results suggest that maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocations in utero leading to infant and early childhood leukemia.

关键词：细胞分化细胞培养的 DNA拓扑异构酶类 Ⅱ型/代谢 DNA结合蛋白质类/药物作用 DNA结合蛋白质类/遗传学膳食外显子胎血/细胞学类黄酮物质/副作用类黄酮物质/药理学造血干细胞/细胞学组蛋白赖氨酸N-甲基转移酶白血病髓样急性/流行病学白血病髓样急性/遗传学髓淋巴细胞性白血病蛋白质前体细胞淋巴母细胞白血病淋巴瘤/流行病学前体细胞淋巴母细胞白血病淋巴瘤/遗传学原癌基因转录因子易位遗传成年人人类婴儿婴儿新生

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BCR/ABL translocation in adult acute lymphoblastic leukemia:: A comparison of conventional and interphase cytogenetic studies

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CANCER GENETICS AND CYTOGENETICS 1999年第1期110卷 19-22页

作者： So, CC Wong, KF Chung, J Kwong, YL Queen Elizabeth Hosp Dept Pathol Hong Kong Peoples R China Queen Mary Hosp Dept Med Hong Kong Peoples R China

Twenty-four adult Chinese patients with de novo acute lymphoblastic leukemia (ALL) were studied for the BCR/ABL translocation using both conventional cytogenetics and fluorescence in situ hybridization (FISH). Fight (33%) patients had the translocation as shown by FISH and all were B-lineage ALL (8/19, 42%). Conventional cytogenetics revealed a t(9;22)(q34;q11) in six of them, but was either unsuccessful, or not done in the other two. Seven of the eight positive cases (88%) showed a breakpoint at the minor breakpoint cluster region (m-BCR), which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). To conclude, the frequency of BCR/ABL translocation in Chinese patients with de novo ALL is comparable to patients in the Western hemisphere, in contrast to a previous report. The predominance of m-BCR/ABL fusion among these Chinese patients with BCR/ABL translocation is also similar to patients in the Western population. Fluorescence in situ hybridization is a sensitive, specific and relatively simple technique for demonstrating this important unfavorable prognostic marker in ALL, even in a routine service laboratory setting. (C) Elsevier Science Inc., 1999. All rights reserved.

关键词：融合蛋白质类 bcr-abl/遗传学基因 abl 分裂间期癌基因蛋白质类/遗传学前体细胞淋巴母细胞白血病淋巴瘤/遗传学蛋白酪氨酸激酶类原癌基因蛋白质类原癌基因蛋白质c-bcr 易位遗传成年人老年人女(雌)性人类男(雄)性中年人

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p190 BCR-ABL rearrangement in chronic myeloid leukemia and acute lymphoblastic leukemia

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CANCER GENETICS AND CYTOGENETICS 1999年第1期113卷 100-102页

作者： Lemes, A Casares, MTG de la Iglesia, S Matutes, E Molero, MT Hosp Univ N Sra del Pino Dept Haematol & Haemotherapy Hematol Serv Las Palmas Gran Canaria 35005 Spain Royal Marsden Hosp Acad Dept Haematol & Cytogenet London England

A minority of chronic myeloid leukemia (CML) cases have breakpoint in the minor cluster region (m-bcr) of the BCR:ABL fusion gene. We report a patient with Ph-positive acute lymphoblastic leukemia and m-bcr breakpoint at diagnosis. The patient was treated with chemotherapy follow ed by an autologous peripheral blood stem cell transplantation, achieving a clinical and hematological complete remission but with persistence of the Philadelphia chromosome. One year later, she developed leukocytosis with a blood picture consistent with CML. She was treated with hydroxyurea and interferon alpha with no response. This is the second case of m-bcr CML reported presenting with features of lymphoid blast crisis or acute lymphoblastic leukemia. (C) Elsevier Science Inc., 1999. All rights reserved.

关键词：骨髓/病理学疾病恶化融合蛋白质类 bcr-abl/遗传学核型分析白血病髓系慢性 BCR-ABL阳性/遗传学前体细胞淋巴母细胞白血病淋巴瘤/遗传学逆转录聚合酶链反应成年人女(雌)性人类

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Cytogenetic abnormalities during clinical, immunophenotypic, and molecular remission in pediatric acute lymphoblastic leukemia

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CANCER GENETICS AND CYTOGENETICS 2000年第1期118卷 9-13页

作者： Sandoval, C Mayer, SP Giamelli, J Farley, T Ozkaynak, MF Tugal, O Jayabose, S New York Med Coll Dept Pediat Valhalla NY 10595 USA

The significance of random cytogenetic abnormalities detected in pediatric acute lymphoblastic leukemia (ALL) during remission is unknown. We studied 10 of 72 consecutive ALL patients who developed cytogenetic abnormalities during clinical remission to determine their effect on remission status. The cytogenetic abnormalities occurred at a median of 14.5 months (range 5-72) from the initial diagnosis. Fire abnormalities were designated as clonal (monosomy 21 in three metaphases and 64 similar to 69, XXY in three metaphases from one patient at different times, and del(20)(q22q13) in three metaphases, add(13)(q34) in two metaphases, and ?del(19)(p11) in two metaphases from three different patients). Ser en abnormalities were previously described: del(5)(q12), del(5)(q33), -7, del(11)(q23), +12, and +13 each in one metaphase, and del(20)(q12q13) in three metaphases). The remaining cytogenetic abnormalities rr ere nonclonal and random. Flow cytometry and analysis of IgH and TcR gene rearrangements showed that all evaluable patients were in immunophenotypic and molecular remission, respectively. Eight patients remain in clinical and molecular remission a median of 9 months (range 7-18) after detecting the cytogenetic abnormality, and the leukemia in two patients has relapsed. During remission, cytogenetic abnormalities may not be a harbinger of leukemia relapse in pediatric ALL;therefore, a wait-and-see approach is prudent. (C) Elsevier Science Inc., 2000. All rights reserved.

关键词：非整倍性染色体畸变/遗传学染色体缺失克隆细胞/免疫学克隆细胞/代谢克隆细胞/病理学流式细胞术基因重排/遗传学基因重排 T淋巴细胞基因免疫球蛋白/遗传学免疫表型分型核型分析白细胞单核/免疫学白细胞单核/代谢白细胞单核/病理学前体细胞淋巴母细胞白血病淋巴瘤/诊断前体细胞淋巴母细胞白血病淋巴瘤/遗传学前体细胞淋巴母细胞白血病淋巴瘤/免疫学前体细胞淋巴母细胞白血病淋巴瘤/病理学预后复发缓解诱导儿童儿童学龄前女(雌)性人类婴儿男(雄)性

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Enhanced detection of chromosomal abnormalities with the use of RxFISH multicolor banding technique

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CANCER GENETICS AND CYTOGENETICS 2000年第2期118卷 108-111页

作者： Zhao, L Hayes, K Glassman, A Univ Texas MD Anderson Canc Ctr Sect Cytogenet Div Pathol & Lab Med Houston TX 77030 USA

Hematological disorders often have complex karyotypes with multiple markers, Proper assignment of chromosome number or aberration or both can be difficult. Specific identification of chromosomal abnormalities aids in the diagnosis and selection of treatment of patients. Fluorescence in situ hybridization (FISH) has been applied to the identification of translocations, markers, and other chromosomal abnormalities in clinical cytogenetics. However, the standard FISH technique is unable to detect the entire genome in a single experiment. This report presents the use of a cross-species comparative genomic hybridization color-banding technique (RxFISH) that permits examination of an entire karyotype at one time. Specimens from two patients, one with acute lymphocytic leukemia (ALL) and the other with multiple myeloma (MM), were studied. Metaphases were prepared by standard culture techniques. Conventional cytogenetic analysis (GTG bonding) showed multiple clones in each of the cases. These clones were hyperdiploid metaphases rr with complex chromosomal abnormalities and multiple markers. The slides were then hybridized with FITC-, Cy-3-, and Cy-5-labeled RxFISH probes;the results were analyzed by a digital imaging system. The RxFISH color banding confirmed the hyperdiploid metaphases and identified multiple chromosomal abnormalities. In the specimen from the patient with ALL, several chromosomes, which had been classified as markers by G-banding, were found to be specific chromosomes. This study suggests that RxFISH con provide more accurate and specific identification of complex chromosomal abnormalities. RxFISH is a useful complement to the clinical cytogenetic laboratory armamentarium. (C) Elsevier Science Inc., 2000. All rights reserved.

关键词：骨髓/超微结构染色体畸变染色体显带/方法原位杂交荧光多发性骨髓瘤/遗传学前体细胞淋巴母细胞白血病淋巴瘤/遗传学人类

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Characterization of chromosomal breakpoints in an ALL patient using cross-species color banding

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CANCER GENETICS AND CYTOGENETICS 2000年第2期119卷 118-120页

作者： Koo, SH Kwon, KC Park, JW Lee, YE Kim, JW Chungnam Natl Univ Hosp Dept Clin Pathol Taejon 301040 South Korea Chungnam Natl Univ Hosp Dept Obstet Taejon 301040 South Korea Dankuk Univ Hosp Dept Clin Pathol Cheonan South Korea

Cross-species color-banded karyotype (Rx-FISH) results were compared with those of conventional G-banded metaphases from the same sample. Breakpoints and karyotype were confirmed as 46,XX,t(8;22)(q24;q11),der(9)t(1;9)(q21;p13) through the novel technology of cross-species color banding in an acute leukemic patient (ALL, L3);the karyotype was 46,XY,t(8;22)(q24;q11),der(9)t(1;9) (q25;p24) by conventional G-banding. (C) 2000 Elsevier Science me. All rights reserved.

关键词：染色体显带/方法染色体人 1对/超微结构染色体人 22对/超微结构染色体人 8对/超微结构染色体人 9对/超微结构致命性结局原位杂交荧光核型分析前体细胞淋巴母细胞白血病淋巴瘤/遗传学前体细胞淋巴母细胞白血病淋巴瘤/病理学易位遗传成年人人类男(雄)性

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MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia

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GENES CHROMOSOMES & CANCER 2000年第3期27卷 264-269页

作者： Sugita, K Taki, T Hayashi, Y Shimaoka, H Kumazaki, H Inoue, H Konno, Y Taniwaki, M Kurosawa, H Eguchi, M Dokkyo Univ Sch Med Dept Pediat Div Hematol Mibu Tochigi 32102 Japan Univ Tokyo Fac Med Dept Pediat Tokyo 113 Japan Dokkyo Univ Sch Med Dept Clin Lab Mibu Tochigi Japan Kyoto Prefectural Univ Med Dept Internal Med 3 Kyoto 602 Japan

We describe a boy with Fanconi anemia (FA) who developed acute lymphoblastic leukemia (ALL) (FAB-L I) followed by acute myeloid leukemia (AML) (FAB-M5) at relapse. The patient was diagnosed with early pre-B-cell ALL without preceding aplastic anemia and was treated with ALL-oriented chemotherapy which included doxorubicin (a total dose of 140 mg/m(2) administered), which is a topoisomerase II inhibitor. Complete remission was obtained, but after 38 weeks AML developed. The karyotype of ALL cells at diagnosis showed 46,XY, and that of AML cells at relapse was 46,XY, t(11;16)(q23;p13). An MLL gene rearrangement and MLL-CBP chimeric mRNA were found in AML, but not in ALL. A diagnosis of FA was confirmed by an increased number of chromosomal breaks and rearrangements in peripheral blood lymphocytes cultured with mitogen in the presence of mitomycin C. We conclude that this FA patient developed ALL followed by a therapy-related t(11;16)-AML resulting in an MLL-CBP fusion. Further examination of such patients would shed light on leukemogenesis in FA patients. (C) 2000 Wiley-Liss, Inc.

关键词：氨基酸序列碱基序列 CREB结合蛋白质染色体人 11对/遗传学染色体人 16对/遗传学 DNA结合蛋白质类/遗传学范科尼贫血/遗传学范科尼贫血/病理学组蛋白赖氨酸N-甲基转移酶核型分析白血病单核细胞急性/遗传学分子序列数据髓淋巴细胞性白血病蛋白质肿瘤继发原发性/遗传学肿瘤继发原发性/病理学核蛋白质类/遗传学表型前体细胞淋巴母细胞白血病淋巴瘤/遗传学前体细胞淋巴母细胞白血病淋巴瘤/病理学原癌基因反式激活因子类/遗传学转录因子易位遗传/遗传学儿童人类男(雄)性

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