Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia.
A large fraction of pediatric pre-B acute lymphoblastoid leukemias (ALL) consistently contain a t(1;19) chromosomal translocation. The t(1;19) translocation results in the production of a chimeric transcription factor containing the N-terminal transactivation domain of E2A fused to the C-terminal DNA-binding homeodomain of Pbx1. Here, we show that the E2A-Pbx1 fusion protein activates the expression of a novel WNT gene, WNT-16. WNT-16 normally is expressed in peripheral lymphoid organs such as spleen, appendix, and lymph nodes, but not in bone marrow. In contrast, high levels of WNT-16 transcripts are present in bone marrow and cell lines derived from pre-B ALL patients carrying the E2A-Pbx1 hybrid gene. Inhibition of E2A-Pbx1 expression leads to a significant decrease in WNT-16 mRNA levels, suggesting that WNT-16 is a downstream target of E2A-Pbx1. Three putative WNT receptors, FZ-2, FZ-3, and FZ-5, are expressed in cells of the B lineage, including pre-B ALL cells aberrantly expressing WNT-16. We propose that a WNT-16-mediated autocrine growth mechanism contributes to the development of t(1;19) pre-B ALL.
McWhirter
J R
JR
Department of Biology, 0366, University of California at San Diego, La Jolla, CA 92093, USA.
Neuteboom
S T
ST
Wancewicz
E V
EV
Monia
B P
BP
Downing
J R
JR
Murre
C
C
D000595:Amino Acid Sequence; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C089847:E2A-Pbx1 fusion protein