Overexpression of LEF1 predicts unfavorable outcome in adult patients with B-precursor acute lymphoblastic leukemia.
Aberrant activation of the Wnt pathway plays a pathogenetic role in various tumors and has been associated with adverse outcome in acute lymphoblastic leukemia (ALL). LEF1, a key mediator of Wnt signaling, has been linked to leukemic transformation, and recurrent mutations of LEF1 have been identified in pediatric T-ALL. Here we evaluated the prognostic significance of LEF1 expression in B-precursor ALL patients. LEF1 expression was determined by quantitative real-time RT-PCR in 282 adult B-precursor ALL patients treated on 06/99 and 07/03 GMALL trials. Patients were grouped into quartiles (Q1-Q4) according to LEF1 expression levels (LEF1 high, Q4; n = 71; LEF1 low, Q1-Q3; n = 211). Patients with high LEF1 expression had a significantly shorter relapse-free survival (RFS) compared with low LEF1 expressers (5-year RFS: LEF1 high, 27%; LEF1 low, 47%; P = .05). Importantly, high LEF1 expression was also associated with inferior RFS in standard-risk patients and was independently predictive for RFS (P = .02) in multivariate analyses for this subgroup. Thus, high LEF1 expression identifies B-precursor ALL patients with inferior RFS, supporting a pathogenetic role of Wnt signaling in ALL. Standard-risk patients with high LEF1 expression might benefit from early treatment modifications and new molecular therapies, including agents targeting the Wnt pathway.
Department of Hematology and Oncology, Charité University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany.
Andrea
A
Kühnl
Nicola
N
Gökbuget
Martin
M
Kaiser
Cornelia
C
Schlee
Andrea
A
Stroux
Thomas
T
Burmeister
Liliana H
LH
Mochmann
Dieter
D
Hoelzer
Wolf-Karsten
WK
Hofmann
Eckhard
E
Thiel
Claudia D
CD
Baldus
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism*; D015331:Cohort Studies; D005091:Exons; D005260:Female; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D016019:Survival Analysis; D015854:Up-Regulation; D055815:Young Adult
D014408:Biomarkers, Tumor; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger