TY - JOUR
T1 - PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway
AU - Zhou, J
AU - Wu, J
AU - Li, Baoyue
AU - Liu, D
AU - Yu, J
AU - Yan, X
AU - Zheng, S
AU - Wang, Johnny
AU - Zhang, Lei
AU - He, F
AU - Li, Q
AU - Chen, A
AU - Zhang, Xiandong
AU - Guan, Y
AU - Zhao, X
AU - Yan, J
AU - Ni, J
AU - Nobrega, MA
AU - Löwenberg, Bob
AU - Delwel, Ruud
AU - Valk, Peter
AU - Kumar, A
AU - Xie, L
AU - Tenen, DG
AU - Huang, G
AU - Wang, QF
PY - 2014
Y1 - 2014
N2 - Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hennatopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.
AB - Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hennatopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.
U2 - 10.1038/leu.2013.384
DO - 10.1038/leu.2013.384
M3 - Article
C2 - 24445817
SN - 0887-6924
VL - 28
SP - 1436
EP - 1448
JO - Leukemia
JF - Leukemia
IS - 7
ER -