TY - JOUR
T1 - Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia
AU - Smeenk, Leonie
AU - Fischer, Maria
AU - Jurado, Sabine
AU - Jaritz, Markus
AU - Azaryan, Anna
AU - Werner, Barbara
AU - Roth, Mareike
AU - Zuber, Johannes
AU - Stanulla, Martin
AU - den Boer, Monique L
AU - Mullighan, Charles G
AU - Strehl, Sabine
AU - Busslinger, Meinrad
N1 - © 2017 The Authors.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-B-cell receptor (BCR) signaling and migration/adhesion, which could contribute to the proliferation, survival, and tissue infiltration of leukemic B cells. Together with similar observations made in human PAX5-ETV6+ B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein that drives B-cell leukemia development.
AB - PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-B-cell receptor (BCR) signaling and migration/adhesion, which could contribute to the proliferation, survival, and tissue infiltration of leukemic B cells. Together with similar observations made in human PAX5-ETV6+ B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein that drives B-cell leukemia development.
KW - Animals
KW - Forkhead Transcription Factors/genetics
KW - Mice
KW - Oncogene Proteins/genetics
KW - PAX5 Transcription Factor/genetics
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology
KW - Proto-Oncogene Proteins c-ets/genetics
KW - Recombinant Fusion Proteins/genetics
KW - Repressor Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85013455941&partnerID=8YFLogxK
U2 - 10.15252/embj.201695495
DO - 10.15252/embj.201695495
M3 - Article
C2 - 28219927
SN - 0261-4189
VL - 36
SP - 718
EP - 735
JO - The EMBO journal
JF - The EMBO journal
IS - 6
ER -