Chalandon, Yves

Jotterand, Martine

Marazzi, Alfio

Rovo, Alicia

Schanz, Urs

Talamo, Anna

Tichelli, André

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LETTER TO THE EDITORHigh hyperdiploid acute lymphoblastic leukemia in adultsshows clonal heterogeneity and chromosomal instabilityat diagnosis and during the course of the diseaseAnna Talamo & Alfio Marazzi & Alicia Rovo &Urs Schanz & André Tichelli & Yves Chalandon &Martine JotterandReceived: 25 July 2011 /Accepted: 22 August 2011 /Published online: 23 September 2011# Springer-Verlag 2011Dear Editor,High hyperdiploidy with 51–67 chromosomes (HeH)constitutes a large cytogenetic subset of B cell precursorchildhood acute lymphoblastic leukemia (ALL) [1]. It ismuch less common in adult B cell precursor ALL where itwas reported in nearly 10% of patients for whom outcomewas improved compared to the other cytogenetic groups,but not as favorable as in children [2, 3]. It is rarely foundin T cell or mature B cell ALL.Automated four-color interphase fluorescence in situhybridization (I-FISH) previously revealed a high level ofclonal aneuploidy heterogeneity in HeH ALL at presentation[4]. Numerical chromosome instability (CIN) was supposedto be at the origin of this heterogeneity. To assess thepresence of clonal heterogeneity and numerical CIN in adultHeH ALL at diagnosis and during disease course, wefocused on a series of ten ALL patients selected accordingto the presence of HeH by conventional cytogenetics, age,and availability of material for four-color I-FISH investiga-tion using probes specific to chromosomes 4, 6, 10, and 17(Supplement 1). Probes were chosen based on the frequentgain of these chromosomes in HeH ALL and its prognosticsignificance [5]. Patients were referred between 1995 and2009 from the university hospitals of Basel, Zurich, Bern,Lausanne and cantonal/regional hospitals of St-Gallen,Aarau, Mendrisio, Bellinzona, and Genolier Clinic. Twopatients were enrolled in the SAKK ALL 33-86/90 [6] andGRAALL 2005 clinical trials, respectively. Ethical approvalfor this project was obtained in accordance with theguidelines of the local Ethical Review Board.Thirty-four samples were analyzed (presentation, 7;hematologic remission, 19; relapse, 8); status of heterogeneityand CIN level were determined (Table 1, Supplement 2).Significant aneuploidies were identified based on cutoffvalues defined according to the Poisson distribution, andcombinations of aneuploidies were considered relevant whenat least one aneuploidy was determined to be significant.Average CIN was determined for all four chromosomestogether and then for each selected chromosome.Approaches used and cutoff levels were reported in detailpreviously [4, 7].Electronic supplementary material The online version of this article(doi:10.1007/s00277-011-1317-x) contains supplementary material,which is available to authorized users.A. TalamoCancer Cytogenetics Unit, Medical Genetics Service,University Hospital and University of Lausanne (CHUV-UNIL),Lausanne, SwitzerlandA. MarazziInstitute of Social and Preventive Medicine,University of Lausanne,Lausanne, SwitzerlandA. Rovo :A. TichelliHematology Department, University Hospital of Basel,Basel, SwitzerlandU. SchanzDepartment of Hematology, University Hospital of Zurich,Zurich, SwitzerlandY. ChalandonHematology Division, University Hospital of Geneva (HUG),Geneva, SwitzerlandM. Jotterand (*)Medical Genetics Service,University Hospital and University of Lausanne (CHUV-UNIL),Av. Pierre Decker 2,CH 1011 Lausanne, Switzerlande-mail: martine.jotterand@chuv.chAnn Hematol (2012) 91:793–796DOI 10.1007/s00277-011-1317-xTable1Clonesinvolvingchromosomes4,6,10,and17atpresentationand/orduringthecourseofdiseaseintenpatientswithhighhyperdiploidacutelymphoblasticleukemia,expressedaspercentagesPatientsClonesexpressedas%1a2a3a4a56789a10Analysis131/05b88/06b363/09b241/05b1086/07b601/02c261/06c331/06c1282/07d1181/08c29/09d540/09d2385/95b1527/97c27/98c158/98c388/02b95/03cNormal18.451.09.853.820.744.286.454.687.042.798.699.424.221.774.296.849.677.4+48.63.8–9.013.05.34.814.33.53.3––1.211.4–2.6––+6–2.66.2428.39.3––3.74.4––17.25.44.4–––+1015.82.28.6––6.42.04.6–3.4––15.03.09.4–45.819.8+175.42.67.6––2.2––3.52.6––––––––+6,+17––7.4––––––2.6––––––––+6,+10–4.020.2––13.9–––7.8––31.214.39.2–1.2–+4,+174.81.2–––––––1.1––––––––+4,+6–2.6–8.834.31.7–––1.6–––3.3––––+4,+1016.83.6–––1.45.624.3–2.8–––3.7––––+10,+179.21.210.8––––––2.0––––––1.2–+4,+10,+1714.02.4–––––––2.1––––––––+4,+6,+10–5.2–––2.1–––5.4–––13.4––––+6,+10,+17–1.823.2––––––6.4––1.0–––––+4,+6,+17–1.6–––––––1.9––––––––+4,+6,+10,+17–7.01.0––––––6.0––––––––+4,+4–1.2–8.6–1.5–––––––1.8––––+4,+4,+6–––13.6––––––––––––––+4,+4,+6,+10–1.4–––––––––––2.8––––+6,+6––––––––––––1.4–––––+6,+6,+10––––––––––––3.01.6––––+4,+6,+6,+10–––––––––––––1.4––––+4,+6,+10,+10–––––––––––––2.5––––+6,+10,+10–––––2.7–––––––2.1––––+6,+10,+17,+17––1.2–––––––––––––––+4,+10,+17,+171.2–––––––––––––––––Otherse5.84.64.02.23.79.41.22.32.33.91.40.65.811.52.80.62.22.8Totalofabnormalclones21(13)29(13)24(15)13(8)18(15)44(34)6(3)8(5)19(16)40(25)7(7)3(3)20(13)56(43)12(9)2(1)8(5)7(6)Valuesinparenthesesarenumbersofverysmallabnormalclones(<1%).Clonesalreadypresentinthepreviousanalysis(<1%)areitalicized.StudypatientsarefurtherdetailedinSupplement1.Four-colorI-FISHusingcentromericprobesspecificforchromosomes4(p-4n1/4,kindlyprovidedbyProf.MarianoRocchi,UniversityofBari,Italy),6,10,and17(D6Z1,D10Z1,andD17Z1,respectively;AmericanTypeCultureCollection,Manassas,VA)wasperformedasformerlydescribed[4]on34bonemarrowsamples,5ofwhichwerereportedinTalamoetal.[7].Probesweredirectlylabeledbynicktranslationwithfourdifferentfluorochromes(Cy3,Cy3.5,DEAC,andFITC).Automatedfour-colorI-FISHanalysiswasrealizedwiththescanningsystemMetafer4/MetaCyte(MetaSystems,Altlussheim,Germany)usingamotorizedepifluorescencemicroscope(AxioImagerZ1;Zeiss,Feldbach,Germany)equippedwitha×40objective(Zeiss).Ineachsample,aminimumof500interphasenucleiwerescored,exceptinonecase(331/06)inwhichonly350nucleiwereavailableforclassificationaPatientsinpartreportedbyTalamoetal.[7](12)bPresentationcRelapsedHematologic(bonemarrow)completeremissioneCumulatedpercentageofverysmallclones(<1%)794 Ann Hematol (2012) 91:793–796High levels of clonal heterogeneity were observed atdiagnosis and during disease course, at relapse particularly.Clones detected at presentation generally reappeared atrelapse, mostly accompanied by newly generated ones(Supplement 3). Whereas the mean total number ofabnormal clones did not clearly differ between diagnosticand relapse samples, the range of their variation did, beingmuch larger at relapse (Table 1). Despite the small numberof patients, a significant correlation was observed betweennumber of abnormal clones and CIN, suggesting that thehigher the instability, the larger the number of abnormalclones (Fig. 1).Data let surmise that the dynamic process at the originof HeH ALL is a complex one leading to coexistence ofsub-clones with different combinations of aneuploidy,whose heterogeneity and variation result from a simultaneouschromosome gain mechanism driven by underlyingchromosome instability and whose evolution will dependon natural selection and acquisition of additional geneticabnormalities [1, 8].Given the poor outcome associated with CIN in solidtumors and myelodysplastic syndromes [9, 10], the natureand extent of clonal heterogeneity at diagnosis may be ofprognostic significance in HeH ALL. This question wouldmerit to be investigated in a large cohort of HeH ALLpatients.Acknowledgments We are indebted to Dr. Mario Bargetzi (CantonalHospital, Aarau), Professor Michel Duchosal (University Hospital,Lausanne), Dr. Valérie Frossard (Valais Hospital, Sion), Dr. JeroenGoede (University Hospital, Zurich), Dr. Urs Hess (Cantonal Hospital,Sankt-Gallen), Dr. Volker Kirchner (Genolier Clinic, Genolier),Dr. Leda Leoncini-Franscini (Oncology Institute of Southern Switzer-land, Bellinzona), Professor Thomas Pabst (University Hospital, Bern),Dr. Olivia Pagani (Regional Hospital, Mendrisio), and Professor OlivierSpertini (University Hospital, Lausanne) for referring patient samples andfor providing clinical data. We are grateful to Dr. Joelle Tchinda(Oncology Diagnostics Laboratories, University Children’s Hospital,Zurich) for providing cytogenetic results from two analyses performed inher laboratory. We thank all the collaborators of the Cancer CytogeneticsUnit (Medical Genetics Service, University Hospital and Universityof Lausanne, Lausanne) and are indebted to Aurélie Diliberto forher technical assistance. We are grateful to Professor Jacques S.Beckmann (Medical Genetics Service, Department of MedicalGenetics, University Hospital and University of Lausanne, Lausanne)and to Dr. Guy van Melle (Institute of Social and Preventive Medicine,University of Lausanne, Lausanne). We thank the GRAALL and SAKKcooperative groups for allowing us to analyze the samples of thepatient who was included in the GRAALL 2005 study. We areindebted to the Mach Gaensslen Stiftung (Schweiz) for the awardto Professor Martine Jotterand.References1. Paulsson K, Johansson B (2009) High hyperdiploid childhoodacute lymphoblastic leukemia. Genes Chromosomes Cancer 48(8):637–660. doi:10.1002/gcc.206712. Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR(2008) Impact of cytogenetics on the outcome of adult acutelymphoblastic leukemia: results of Southwest Oncology Group9400 study. Blood 111(5):2563–2572. doi:10.1182/blood-2007-10-1161863. Moorman AV, Chilton L, Wilkinson J, Ensor HM, Bown N,Proctor SJ (2010) A population-based cytogenetic study of adultswith acute lymphoblastic leukemia. Blood 115(2):206–214.doi:10.1182/blood-2009-07-2321244. Blandin AT, Muhlematter D, Bougeon S, Gogniat C, Porter S,Beyer V, Parlier V, Beckmann JS, van Melle G, Jotterand M(2008) Automated four-color interphase fluorescence in situhybridization approach for the simultaneous detection ofspecific aneuploidies of diagnostic and prognostic significancein high hyperdiploid acute lymphoblastic leukemia. CancerGenet Cytogenet 186(2):69–77. doi:10.1016/j.cancergencyto.2008.06.0085. Sutcliffe MJ, Shuster JJ, Sather HN, Camitta BM, Pullen J,Schultz KR, Borowitz MJ, Gaynon PS, Carroll AJ, HeeremaNA (2005) High concordance from independent studies by theChildren’s Cancer Group (CCG) and Pediatric Oncology Group(POG) associating favorable prognosis with combined trisomies4, 10, and 17 in children with NCI Standard-Risk B-precursorAcute Lymphoblastic Leukemia: a Children’s Oncology Group(COG) initiative. Leukemia 19(5):734–740. doi:10.1038/sj.leu.24036736. Wernli M, Tichelli A, von Fliedner V, Brun del Re G, ChapuisB, Fey MF, Fopp M, Gmur J, Grob JP, Jacky E et al (1994)Intensive induction/consolidation therapy without maintenancein adult acute lymphoblastic leukaemia: a pilot assessment.Working Party on Leukaemia of the Swiss Group forEpidemiologic and Clinical Cancer Research (SAKK). Br JHaematol 87(1):39–43Fig. 1 Number of abnormal clones and CIN values (%) in 18 bonemarrow samples from 10 patients with high hyperdiploidy acutelymphoblastic leukemia at disease presentation (black points), hema-tological complete remission (white points) and relapse (gray points).The correlation between number of abnormal clones and CIN levelwas measured using the Spearman correlation coefficient. There is anincreasing curvilinear trend, as suggested by the broken line (anonparametric smooth). The Spearman coefficient (0.89) was highlysignificant (p<10-6).Ann Hematol (2012) 91:793–796 7957. Talamo A, Chalandon Y, Marazzi A, Jotterand M (2010) Clonalheterogeneity and chromosomal instability at disease presentation inhigh hyperdiploid acute lymphoblastic leukemia. Cancer GenetCytogenet 203(2):209–214. doi:10.1016/j.cancergencyto.2010.09.0058. Greaves M (2009) Darwin and evolutionary tales in leukemia. TheHam-Wasserman Lecture. Hematology Am Soc Hematol EducProgram:3–12. doi:10.1182/asheducation-2009.1.39. Nakamura H, Saji H, Idiris A, Kawasaki N, Hosaka M, Ogata A,Saijo T, Kato H (2003) Chromosomal instability detected byfluorescence in situ hybridization in surgical specimens of non-small cell lung cancer is associated with poor survival. ClinCancer Res 9(6):2294–229910. Heilig CE, Loffler H, Mahlknecht U, Janssen JW, Ho AD,Jauch A, Kramer A (2010) Chromosomal instability corre-lates with poor outcome in patients with myelodysplasticsyndromes irrespectively of the cytogenetic risk group. JCell Mol Med 14(4):895–902. doi:10.1111/j.1582-4934.2009.00905.x796 Ann Hematol (2012) 91:793–796

High hyperdiploid acute lymphoblastic leukemia in adults shows clonal heterogeneity and chromosomal instability at diagnosis and during the course of the disease

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High hyperdiploid acute lymphoblastic leukemia in adults shows clonal heterogeneity and chromosomal instability at diagnosis and during the course of the disease

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