MLL mutation

CLINICAL OBSERVATIONS,INTERVENTIONS,AND THERAPEUTIC TRIALS

AML with11q23/MLL abnormalities as defined by the WHO classification: incidence,partner chromosomes,FAB subtype,age distribution,and prognostic impact in an unselected series of1897cytogenetically analyzed AML cases Claudia Schoch,Susanne Schnittger,Mirjam Klaus,Wolfgang Kern,Wolfgang Hiddemann,and Torsten Haferlach

Acute myeloid leukemia(AML)cases with 11q23abnormalities involving the MLL gene comprise one category of recurring genetic abnormalities in the WHO classifi-cation.In an unselected series of1897 AML cases,54patients with an11q23/ MLL rearrangement were identified,result-ing in an incidence of2.8%.The incidence of AML with MLL rearrangement was sig-nificantly higher in therapy-related AML (t-AML)than in de novo AML(9.4%vs 2.6%,P<.0001).The frequency of MLL rearrangements was significantly higher in patients younger than60years(5.3%

vs0.8%,P<.0001).While the incidence

of MLL rearrangements in AML M4,M5a,

and M5b was 4.7%,33.3%,and15.9%,

respectively,it was found in only0.9%of

all other French-American-British(FAB)

subtypes(P<.0001).Compared with AML

with intermediate karyotype,AML with

11q23/MLL rearrangement had a worse

outcome,which was rather comparable

with AML with unfavorable karyotype.

Compared with t-AML,the median overall

survival(OS)of de novo AML with MLL

rearrangement was significantly better

(2.5vs10months,P؍.0143).No signifi-

cant differences in median OS were ob-

served between cases with t(9;11)com-

pared with all other MLL rearrangements

(10.0vs8.9months,P؍.36).In conclu-

sion,the category AML with11q23/MLL

abnormalities accounts for 2.8%of un-

selected AML,is closely associated with

monocytic differentiation,and has a dismal

prognosis.(Blood.2003;102:2395-2402)

©2003by The American Society of Hematology

Introduction

Classification of acute myeloid leukemia(AML)has been based on cytomorphology and cytochemistry since the introduction of the French-American-British(FAB)classification in1976.1As other techniques such as immunophenotyping as well as cytoge-netics and moleculargenetics contributed to the definition of AML subtypes,the FAB classification was updated accord-ingly.2-5In parallel,the MIC classification was published in 1986,which used morphology,immunophenotype,and cytoge-netics to define subgroups in AML.6This system already proposed a category M5a/t(11q),although no detailed studies are quoted to underline this decision.In2001the WHO classification for tumors of hematopoietic and lymphoid tissues was proposed.7In an attempt to define biologic homogenous entities that have clinical relevance,morphologic,immunophe-notypic,genetic,and clinical features were incorporated into the classification of AML.8The WHO classification of AML encompasses4major categories:(1)AML with recurring genetic abnormalities,(2)AML with multilineage dysplasia, (3)AML,therapy related,and(4)AML not otherwise catego-rized.In thefirst category the following subcategories are defined:(a)AML with t(8;21)(q22;q22);AML1/ETO,(b)AML with abnormal bone marrow eosinophils inv(16)(p13q22)or t(16;16)(p13;q22);CBFB/MYH11,(c)acute promyelocytic leu-kemia(AML with t(15;17)(q22;q12);PML-RARA and variants), and(d)AML with11q23/MLL abnormalities.While a,b,and c are homogenous entities on the cytogenetic as well as at the molecular level and show close correlations with morphology, AML with11q23/MLL abnormalities is heterogeneous due to the different partner chromosomes/partner genes.More than50 partners of the MLL gene have been described and more than30 partner genes have already been cloned and analyzed at the molecular level.9,10Therefore,it was the aim of this study to characterize this subcategory of AML on the basis of a series of 1897unselected and cytogenetically analyzed AML cases at diagnosis with special emphasis on the overall incidence,the different partner chromosomes,FAB subtype,age distribution, and prognostic impact.

Patients,materials,and methods

Patient material

Between January1996and August2001,cytogenetics were successfully performed in our laboratory on1897patients with newly diagnosed AML who were the basis for this study without any further selection.This cohort represents98.2%of all AML cases sent to our laboratory for cytogenetic analysis.Because no or only an insufficient number of metaphases was obtained(Ͻ15metaphases if no clonal chromosomal abnormalities were detected),1.8%were scored not evaluable.Altogether54cases with an 11q23abnormality involving the MLL gene were identified.In each case the rearrangement of the MLL gene was proved either by reverse transcription–polymerase chain reaction(RT-PCR)and/orfluorescence in situ hybridiza-tion(FISH)with an MLL probe.

From the Laboratory for Leukemia Diagnostics,Department of Internal Medicine III,University Hospital Grosshadern,Ludwig-Maximilians-University, Munich,Germany.

Submitted February10,2003;accepted June5,2003.Prepublished online as Blood First Edition Paper,June12,2003;DOI10.1182/blood-2003-02-0434. Reprints:Claudia Schoch,Laboratory for Leukemia Diagnostics,Department of Internal Medicine III,University Hospital Grosshadern,Ludwig-Maximilians-University of Munich,Marchioninistr15,81377Mu¨nchen,Germany;e-mail: claudia.schoch@med3.med.uni-muenchen.de.

The publication costs of this article were defrayed in part by page charge payment.Therefore,and solely to indicate this fact,this article is hereby marked‘‘advertisement’’in accordance with18U.S.C.section1734.

©2003by The American Society of Hematology

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BLOOD,1OCTOBER2003⅐VOLUME102,NUMBER7