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©Ferrata Storti Foundation Cytogenetics original paper haematologica 2001; 86:1245-1253 Fluorescence in situ hybridization http://www.haematologica.it/2001_12/1245.htm study of TEL/AML1 fusion and other abnormalities involving TEL and AML1 genes. Correlation with cytogenetic findings and prognostic value in children with acute lymphoblastic leukemia ANGEL MARTÍNEZ-RAMÍREZ,* MIGUEL URIOSTE,* # @ TRINIDAD CONTRA,°ANGELES CANTALEJO, AMANDIO TAVARES, *Departamento de Genética Humana, Programa de Patología JOSÉ ANTONIO PORTERO,^ BLANCA LÓPEZ-IBOR,§ Mo ecular, Centro Nacional de Investigaciones Oncológicas (CNIO), MERCEDES BERNACER,**CARLOS SOTO,** Instituto de Salud Carlos III, Madrid; Spain. ,°Departamento de JUAN CRUZ CIGUDOSA,* JAVIER BENÍTEZ* Oncología, Hospital Niño Jesús, Madrid; Spain. #Servicio de Hematologgía, Hospital Infantil Gregorio Marañón, Madrid; Spain. Correspondence: Angel Martínez-Ramírez, MD, Dpto. de Genética @Centro Genética Clínica, Porto; Portugal. ^Servicio de Hema- Humana, Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas (CNIO), Ctra. Majadahonda-Pozuelo, tología, Hospital Virgen de la Concha, Zamora; Spain. §Servicio de Km. 2, 28220 Majadahonda, Madrid, Spain. Fax: international Hematología, Hospital de San Rafael, Madrid; Spain. **Servicio de +34.9.15097055. E-mail: [email protected] Hematología, Fundación Jiménez Díaz (FJD), Madrid; Spain. Background and Objectives. The TEL/AML1 fusion these additional AML1 or TEL FISH alterations is the most common genetic abnormality found in (p<0.02), which could be related to the presence of childhood acute lymphoblastic leukemias (ALL). specific karyotypes. Although it is very difficult to identify by conven- tional cytogenetic techniques it can be readily Interpretations and Conclusions. The frequency of detected using fluorescence in situ hybridization TEL/AML1 fusion is similar to that found in other (FISH). We carried out cytogenetic and FISH stud- populations (17%). We found that FISH analysis of ies on 42 children with ALL in order to know the fre- AML and TEL is related to the evolution of the dis- quency of this translocation in our population, the ease. The absence of alterations in these genes incidence of TEL and/or AML1 gene alterations, and revealed by FISH could be indicative of bad prog- their correlation with clinical evolution and progno- nosis, while the presence of alterations is related to sis. In addition, we performed reverse transcription a good evolution. Our results suggest that inter- polymerase chain reaction (RT-PCR) in some cases, phase FISH analysis to search for alterations in AML confirming the feasibility of FISH techniques in the and TEL genes could be extremely useful for com- detection of this translocation. plementing cytogenetic studies and for providing additional information about the possible outcome Design and Methods. Bone marrow samples were of the disease in patients with ALL. obtained from 42 childhood ALL patients. The copy ©2001, Ferrata Storti Foundation number of AML1 and TEL genes were studied using fluorescent in situ hybridization with a dual color Key words: acute lymphoblastic leukemia, TEL/AML1 DNA probe specific for the AML1 and TEL genes. fusion gene, AML1 amplification, t(12;21), Results. We found a frequency of TEL/AML1 fusion fluorescence in situ hybridization. of 17% in our sample. Double TEL/AML1 fusion, lack of TEL signal and extra AML1 signals were fre- he translocation 12;21, which involves the TEL quent additional FISH abnormalities. Duplication of gene on chromosome 12p13 and the AML1 a chromosomal complement, deletion of chromo- Tgene on chromosome 21q22, is associated some 12p arm, and polysomies of chromosome 21 with acute lymphoblastic leukemias (ALL), espe- are plausible explanations for these additional FISH cially in children. Although it is difficult to identi- findings. However, a relatively high proportion of our fy by conventional cytogenetic techniques, cases (9.5%) presented specific amplification of TEL/AML1 fusion can be readily detected using flu- AML1. A statistically significant difference in prog- orescence in situ hybridization (FISH).1,2 FISH nosis was found between patients with and without analysis has shown that TEL/AML1 fusion is the haematologica vol. 86(12):december 2001 1246 A. Martínez-Ramírez et al. most common genetic abnormality in childhood of them with the BFM95 protocol, the remaining ALL, being found in about 25% of cases. It also with the BFM90 protocol).26 3,4,5 occurs in 3-4% of adult ALL cases. The translo- Immunophenotypic studies cation is associated with an early onset of the dis- Flow cytometry immunophenotypic analysis was ease, a B-lineage immunophenotype, and a good performed in all cases, using a variable panel of a prognosis.6 Extra cytogenetic abnormalities, associated with large number of antibodies specific for the CD2, CD3, the t(12;21), are frequently found. The most com- CD4, CD7, CD8, CD10, CD19, CD20, CD22, CD34, mon structural and numerical aberrations are 12p CD79, tdt and HLA-DR antigens and immunoglobu- rearrangements and trisomy 21, respectively.7 A lin κ light chains (Ig M and Ig S) (Dako A/S, Copen- double fusion signal, detected by FISH, is another hagen, Denmark). common finding in patients with t(12;21).8,9 Dele- Conventional cytogenetics tions involving the untranslocated TEL allele, Bone marrow samples were incubated in RPMI detected by cytogenetic and/or FISH techniques, 1640 with 20% fetal calf serum for 1 day at 37ºC. are also often found in patients with TEL/AML1 Cells were exposed to colcemid (0.1 µg/mL) for 1.5 fusion.3,10,11,12,13 Although deletions on the short arm h at 37ºC and harvested routinely. Metaphase chro- of chromosome 12 are recurrent alterations found mosomes were GTG-banded by a conventional in a wide range of hematologic neoplasias, the trypsin-Giemsa technique and karyotyped accord- leukemogenic role of the genes located there, TEL ing to the International System for Human Cyto- 14 and p27, is unknown. genetic Nomenclature.27 The AML1 gene is also involved in many chromo- somal aberrations associated with hematologic dis- Fluorescence in situ hybridization (FISH) orders. More than 40 different patterns of translo- Chromosome spreads were prepared directly cations or rearrangements involving the 21q22 from the same samples used for conventional region have been described,15 and amplification of analysis and left overnight at room temperature. the 21q22 region in pediatric patients with ALL has Slides were placed on a plate at 90ºC for 10 min, also been detected by comparative genomic dehydrated through a series of ethanol washes and hybridization (CGH).16 Thus, the AML1 gene could denatured in the presence of the probe on a plate have an important role in the 21q22 amplicon in at 75ºC for 1 min. The TEL/AML1 dual-color translo- childhood ALL.16,17 cation FISH probe (Vysis, London, UK) was used for The incidence of TEL-AML1 fusion ranges between the detection of the TEL/AML1 rearrangement. At 18 and 30% in B-lineage childhood ALL, and is sim- least 200 interphase nuclei were analyzed for each ilar in different populations.6,11,18-24 In marked con- case. Positive and negative controls from the REH trast to these findings, a recent report has revealed cell-line and five normal individuals, respectively, a very low frequency (3%) of TEL-AML1 fusion in a were used. Cell images were captured using a CCD Spanish population,25 thereby suggesting that geo- camera (Photometrics SenSys camera) connected graphic differences exist. to a personal computer running the Chromofluor Here we present cytogenetic and FISH studies car- image analysis system (Applied Imaging Ltd.). ried out on a series of 42 pediatric patients with ALL at presentation. In our Spanish series, we found a RNA preparation frequency of TEL/AML1 fusion similar to that previ- Total RNA was prepared either by the guanidini- ously described in American, European and Oriental um thiocyanate phenol-chloroform extraction populations. Furthermore, we identified a high fre- method or by using the TRI REAGENT Kit (Molecu- quency of additional abnormalities of AML1 and/or lar Research Centre, INC) according to the manu- TEL genes that can be correlated with the prognosis facturer's recommendations. One microgram of cell of the disease. line RNA or 1-2 mg of patient RNA were reverse transcribed with 1.5 units of AMV Reverse Tran- Design and Methods scriptase (Promega Madison, USA). Following Patients denaturation at 80ºC for 5 min, the cDNA synthe- Bone marrow samples were obtained from 42 chil- sis was carried out at 42ºC for 60 min using ran- dren diagnosed as having acute lymphoblastic dom hexamers (Amersham Pharmacia Biotech Inc.) leukemia between 1995 and 2001. All patients were in a total volume of 40 µL. Subsequently, the cDNA classified according to the French-American-British was heated to 94ºC for 10 min to inactivate the (FAB) criteria and treated by standard protocols (most reverse transcriptase and was then stored at -20ºC. haematologica vol. 86(12):december 2001 Abnormalities of TEL and AML1 genes and prognosis 1247 Table 1. Clinical and cytogenetic data from 42 children with ALL at diagnosis. Clinical data Cytogenetic data Immunophenotype FISH No. B markers T markers Type Sex/Age Dx CR Survival Conventional cytogenetics TEL/AML1 TEL AML1 1+-pre-B F/13 09/83 Yes †159m 46,XX,t(9;22)(q34;q11)/46,XXn n n 2+-pre-B M/13 05/96 No †8m ND n n n 3+-pre-B F/10 05/96 Yes †8m 46, XX,t(9;22)(q34;q11) n n n 4+-pre-B F/6 06/96 Yes 44m + 46,XX n n n 5+-pre-B M/4 09/98 Yes †9m
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