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Chromosomal Aberration of the 11Q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation Results in 378 Adult Patients

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Chromosomal Aberration of the 11Q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation Results in 378 Adult Patients Hematopathology / 11Q23 ABERRATIONS AND MLL GENE STATUS IN ACUTE LEUKEMIA Chromosomal Aberration of the 11q23 Locus in Acute Leukemia and Frequency of MLL Gene Translocation Results in 378 Adult Patients M. Christina Cox, MD, PhD,1 Paola Panetta,1 Francesco Lo-Coco, MD,1 Giovanni Del Poeta, MD,1 Adriano Venditti, MD, PhD,1 Luca Maurillo, MD, PhD,1 M. Ilaria Del Principe, MD, PhD,1 Alessandro Mauriello, MD,2 Lucia Anemona, MD, PhD,2 Antonio Bruno,1 Carla Mazzone, MD,1 Downloaded from https://academic.oup.com/ajcp/article/122/2/298/1759501 by guest on 23 September 2021 Paolo Palombo, MD,3 and Sergio Amadori, MD, PhD1 Key Words: MLL; 11q23; AML; Acute myeloblastic leukemia; ALL; Acute lymphoblastic leukemia; AL; Acute leukemia; Chromosomal aberrations; FISH; Fluorescence in situ hybridization; 11q22~25 DOI: 10.1309/RX27R8GJQM330C22 Abstract Structural abnormality of the 11q23 band (11q23+) Structural abnormality of the 11q23 band (11q23+) bearing the MLL gene translocation (MLL+) is a recurrent chro- bearing the MLL gene translocation (MLL+) is a mosome change in leukemia described in acute myeloblastic recurrent chromosome change observed in 3% to 7% of leukemia (AML) and in acute lymphoblastic leukemia (ALL), acute lymphoblastic leukemias and in 3% to 4% of with a peak incidence in infant leukemia.1,2 A proposal by the acute myeloblastic leukemias. The resolution of World Health Organization specifies a separate category for conventional cytogenetics (CC) in detecting 11q23 AML with 11q23+/MLL+.3 This notion has been supported rearrangement is limited when the translocative partner recently by biologic studies: microarray analyses have shown has a telomeric location; furthermore, CC can barely that MLL+ acute leukemias (ALs) have a peculiar gene- discriminate between true 11q23+/MLL+ and profiling pattern that distinguishes them from all other ALs and rearrangements clustering within the 11q22~25 region that MLL+ leukemic blasts resemble very immature progenitor without MLL involvement (MLL–). We characterized a cells.4 Furthermore, these studies showed that MLL+ leukemias series of 378 consecutive patients with adult acute are a separate entity when compared with AML with MLL leukemia by using CC, fluorescence in situ partial tandem duplication (MLL-PTD), a recently identified hybridization (FISH), and multiplex karyotyping (M- genetic aberration observed in a sizable proportion of AMLs.5 FISH) analysis. Our aim was to define the frequency of Extensive cytogenetic and molecular studies have shown cryptic MLL+ cases and the frequency of MLL+ within that 11q23/MLL is a highly promiscuous locus: more than 50 11q22~25+ cases. As expected, FISH was more chromosomal loci have been described as 11q23 chromo- sensitive than CC in detecting MLL+ cases, but rather some partners, whereas more than 30 MLL partner genes unexpectedly, 9 (45%) of 20 patients with 11q22~25+ have been characterized.6 It also should be mentioned that were MLL–. A better characterization of t(11q23) might involve genes other than MLL7 and that 11q22~25+/MLL– leukemias is relevant for the conventional cytogenetics can barely discriminate between identification of new, recurrent translocations. true 11q23+/MLL+ and rearrangements clustering within the Moreover, these cases should be readily distinguishable 11q22~25 region without MLL involvement.8 from 11q23+/MLL+ cases. We recommend that Because t(9;11)(p21;q23) bearing the MLL/AF9 gene karyotypic analysis always be complemented by fusion in AML and t(4;11) with MLL/AF4 gene fusion in molecular or FISH methods to unravel MLL infant leukemia are the most common types,6 these transloca- rearrangements. tions often are referred to as classic translocation, whereas all other variants are reported as v11q23. 11q23+/MLL+ is described in 3% to 4% of AML cases and is more frequent in younger subjects with de novo (5%-7%) AML or with t-AML (10%-15%) evolving after chemotherapy. 298 Am J Clin Pathol 2004;122:298-306 © American Society for Clinical Pathology 298 DOI: 10.1309/RX27R8GJQM330C22 Hematopathology / ORIGINAL ARTICLE In older patients with AML (60 years or older), it is observed in newly diagnosed patients with AML and ALL (n = 170). rarely.9 The majority of 11q23+/MLL+ AML cases have mono- Furthermore, all residual archival AL samples (n = 208) also cytoid differentiation features and are classified in the M4 and were analyzed by FISH for MLL rearrangement. Overall, M5 leukemia French-American-British (FAB) subtypes.10 In 378 samples from consecutive patients with newly diagnosed adult ALL, the overall incidence of 11q23+/MLL+ is reported AL were the basis of this study without further selection. to be around 3% to 7%,11 but in pro-B-cell ALL, it accounts for Leukemia was classified according to FAB criteria21,22 and more than 30% of chromosomal aberrations.12,13 immunophenotyping of leukemic cells.23 While t(4;11) ALL has an established dismal prognosis, Of the 378 cases, 327 (86.5%) were classified as AML, the clinical outcome of 11q23+/MLL+ AML is more hetero- 47 (12.4%) as ALL, and 4 (1.1%) as biphenotypic leukemia. geneous.14-16 The Medical Research Council14 and the Leukemia subtypes are summarized in ❚Table 1❚. Southwest Oncology Group15 classify the risk for patients In 56 (17.1%) of 327 patients, AML had developed after Downloaded from https://academic.oup.com/ajcp/article/122/2/298/1759501 by guest on 23 September 2021 with AML with t(9;11) as intermediate and poor, respec- a primary malignancy; all ALL and B-cell AL cases were de tively. Even more disagreement surrounds the prognostic novo. The mean age was 58 years in patients with AML relevance of classic t(9;11) vs v11q23: some clinical trials (range, 14-81 years), 33 years in ALL (range, 14-74 years), reported that patients with t(9;11) fared better than patients and 26 years in B-cell AL (range, 19-32 years). with v11q23,16,17 whereas other studies failed to identify All patients with AML who were eligible for intensive differences.9,14 These discrepancies probably reflect the chemotherapy were enrolled in consecutive trials of the marked biologic heterogeneity of 11q23 aberrations. Further- GIMEMA (Gruppo Italiano Malattie ematologiche more, because many v11q23 translocations are rare translo- dell’adulto)–European Organization for Research and Treat- cations, the clinical impact of specific single variants is diffi- ment of Cancer cooperative group (AML8, AML10, AML12, cult to extrapolate, even from large studies on 11q23 AL.14-16 AML11, AML13, AML15). Patients younger than 60 years Recently, the combined use of conventional cytoge- who had an HLA-identical sibling donor underwent allo- netics, reverse transcriptase–polymerase chain reaction (RT- geneic bone marrow or peripheral blood transplantation. ALL PCR), Southern blot analysis, and fluorescence in situ patients eligible for intensive treatment were enrolled in the hybridization (FISH) in limited AL series has revealed that conventional induction regimen ALL 0288 (GIMEMA)24; discrepant results with MLL involvement might become some patients with standard-risk and most with high-risk evident,18 and a high incidence of patients with cryptic disease were given intensive induction chemotherapy based MLL+ leukemia were observed in 2 pediatric series.19,20 on high-dose cytarabine and mitoxantrone plus prednisone, Because the majority of clinical trials include only karyotype which, after a similar consolidation cycle, was followed by data,14-16 it is reasonable to speculate that beyond biologic autologous or allogeneic transplantation.25 heterogeneity, these discrepancies also are due partly to the low accuracy of conventional cytogenetics. ❚Table 1❚ We describe our findings in a series of 378 consecutive Distribution of Patients With AL in Subcategories and cases of adult AL, studied with conventional cytogenetics, Incidence of MLL+ and 11q22~25+/MLL– Cases Within * FISH, and multiplex karyotyping (M-FISH) analysis. The Different ALs aim of the study was to define the incidence of cryptic MLL Subcategory No. of Patients MLL+ 11q22~25/MLL– gene translocation and the incidence of MLL gene rearrange- Acute myeloblastic leukemia ment within 11q22~25+ cases. M0 27 2 (7) 2 (7) M1 69 1 (1) 1 (1) M2 82 1 (1) 0 (0) M3 25 0 (0) 0 (0) M4 47 2 (4) 1 (2) Materials and Methods M5a 30 6 (20) 1 (3) M5b 30 3 (10) 0 (0) M6 13 0 (0) 2 (15) Cases M7 4 0 (0) 0 (0) Acute lymphoblastic leukemia Between November 1992 and September 2003, 478 AL Pro-B cell 4 0 (0) 0 (0) samples from newly diagnosed adult patients (older than 14 Pre-B cell, common 25 0 (0) 1 (4) Burkitt 7 0 (0) 0 (0) years) were sent to our laboratory for conventional cytoge- Pre-T cell 4 0 (0) 0 (0) netic analysis. Conventional cytogenetics was done T cell 7 0 (0) 0 (0) B-cell AL 4 0 (0) 1 (25) following standard methods, and residual pellets were stored Total 378 15 (4.0) 9 (2.4) at –20°C in Carnoy solution. From January 2000, FISH analysis with the MLL gene probe (Vysis, Downers Grove, AL, acute leukemia. * Data are given as number (percentage). AMLs are listed according to the French- IL) was combined routinely with conventional cytogenetics American-British Classification. © American Society for Clinical Pathology Am J Clin Pathol 2004;122:298-306 299 299 DOI: 10.1309/RX27R8GJQM330C22 299 Cox et al / 11Q23 ABERRATIONS AND MLL GENE STATUS IN ACUTE LEUKEMIA Conventional Cytogenetics at room temperature in 2× SSC for 1 minute. Slides then Samples obtained before February 1997 were cultured were counterstained with 4'-6'-diamidino-8-phenylindole at 24 and 48 hours without synchronization. Starting from (DAPI), 0.1 µg/mL (Vysis), and analyzed using an Olympus 1997, 3 short-term cell cultures were set up from each BX2 microscope (Olympus, Tokyo, Japan) equipped with a harvest: 2 synchronized cultures at 24 and 48 hours and 1 100-W lamp and a complete set of filters.
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