Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.
OBJECTIVE
Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved.


METHODS
Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction.


RESULTS
3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3).


CONCLUSIONS
Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.
Lugthart
Sanne
S
Erasmus University Medical Center, Rotterdam, The Netherlands.
Gröschel
Stefan
S
Beverloo
H Berna
HB
Kayser
Sabine
S
Valk
Peter J M
PJ
van Zelderen-Bhola
Shama Lydia
SL
Jan Ossenkoppele
Gert
G
Vellenga
Edo
E
van den Berg-de Ruiter
Eva
E
Schanz
Urs
U
Verhoef
Gregor
G
Vandenberghe
Peter
P
Ferrant
Augustin
A
Köhne
Claus-Henning
CH
Pfreundschuh
Michael
M
Horst
Heinz A
HA
Koller
Elisabeth
E
von Lilienfeld-Toal
Marie
M
Bentz
Martin
M
Ganser
Arnold
A
Schlegelberger
Brigitte
B
Jotterand
Martine
M
Krauter
Jürgen
J
Pabst
Thomas
T
Theobald
Matthias
M
Schlenk
Richard F
RF
Delwel
Ruud
R
Döhner
Konstanze
K
Löwenberg
Bob
B
Döhner
Hartmut
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D002893:Chromosomes, Human, Pair 3; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D009006:Monosomy; D015999:Multivariate Analysis; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D011519:Proto-Oncogenes; D012074:Remission Induction; D014157:Transcription Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C484449:EVL protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors