PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway

Abstract

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 hematopoietic 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.

PU.1 affects proliferation of the human acute myeloid leukemia U937 cell line by directly regulating MEIS1

“…These studies indicated that the presence of PU.1 activity may be required to favor the growth of myeloid leukemia stem cells. Previous studies have reported that PU.1 demonstrated an essential expression and activated a well-known oncogene MEIS1 pathway in MLL, accompanied by MEIS1 overexpression (16). In addition, the expression of the PU.1 gene and the survival rate appeared to be inversely associated in human AML samples with MLL rearrangement (16).…”

“…In addition, there is a positive association between the expression of PU.1 and MEIS1 in MLL patients, and the regulation of MEIS1 by PU.1 is central to the pathogenesis of leukemia harboring MLL rearrangements (16). However, the function of PU.1 and its mechanism in non-MLL remains unclear.…”

“…Importantly, the present data initially revealed that PU.1 exhibited strong enrichment in the MEIS1 promoter region using in vivo and in vitro assays. Notably, this PU.1 binding genomic locus in U937 cells varies from the regulation via intron regions in MLL (16), indicating that MEIS1 regulatory sites by PU.1 may be multiple in various type of leukemia.…”

“…Previous studies have reported that PU.1 demonstrated an essential expression and activated a well-known oncogene MEIS1 pathway in MLL, accompanied by MEIS1 overexpression (16). In addition, the expression of the PU.1 gene and the survival rate appeared to be inversely associated in human AML samples with MLL rearrangement (16). Despite the requirement of PU.1 in the development of MLL, as a pro-tumor gene, the key function of PU.1 may not be limited to MLL in AML.…”

“…Previous studies have revealed that PU.1 is essential for leukemia harboring mixed lineage leukemia (MLL) gene rearrangements (16), which is characterized by high expression of the homeobox oncogene MEIS1 (17). In addition, there is a positive association between the expression of PU.1 and MEIS1 in MLL patients, and the regulation of MEIS1 by PU.1 is central to the pathogenesis of leukemia harboring MLL rearrangements (16).…”