A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis.
Canonical Wnt signaling is critically involved in normal hematopoietic development and the self-renewal process of hematopoietic stem cells (HSCs). Deregulation of this pathway has been linked to a large variety of cancers, including different subtypes of leukemia. Lef-1 is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. Here, we demonstrate Lef-1 expression in murine HSCs as well as its expression in human leukemia. Mice transplanted with bone marrow retrovirally transduced to express Lef-1 or a constitutive active Lef-1 mutant showed a severe disturbance of normal hematopoietic differentiation and finally developed B lymphoblastic and acute myeloid leukemia (AML). Lef-1-induced AMLs were characterized by immunoglobulin (Ig) DH-JH rearrangements and a promiscuous expression of lymphoid and myeloid regulatory factors. Furthermore, single cell experiments and limiting dilution transplantation assays demonstrated that Lef-1-induced AML was propagated by a leukemic stem cell with lymphoid characteristics displaying Ig DH-JH rearrangements and a B220(+) myeloid marker(-) immunophenotype. These data indicate a thus far unknown role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development.
Petropoulos
Konstantin
K
Department of Medicine III, Klinikum Grosshadern, D-81377 Munich, Germany.
Arseni
Natalia
N
Schessl
Christina
C
Stadler
Christiane R
CR
Rawat
Vijay P S
VP
Deshpande
Aniruddha J
AJ
Heilmeier
Bernhard
B
Hiddemann
Wolfgang
W
Quintanilla-Martinez
Leticia
L
Bohlander
Stefan K
SK
Feuring-Buske
Michaela
M
Buske
Christian
C
D000818:Animals; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D012333:RNA, Messenger; D051153:Wnt Proteins