PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway.
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.
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
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J
Zhou
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
J
J
Wu
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China [3] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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B
Li
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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D
Liu
Shanghai Center for Bioinformation Technology, Shanghai, People's Republic of China.
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J
Yu
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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X
Yan
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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S
Zheng
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.
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J
Wang
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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L
Zhang
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
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L
Zhang
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
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F
He
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
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Q
Li
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China [3] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
A
A
Chen
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Y
Y
Zhang
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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X
Zhao
Respiratory Department, 2nd Branch of First Hospital of Jilin University, Changchun, People's Republic of China.
Y
Y
Guan
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
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X
Zhao
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
J
J
Yan
Tongji Medical College of Huazhong University of Science & Technology, Wuhan, People's Republic of China.
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J
Ni
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
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MA
Nobrega
Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
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B
Löwenberg
Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
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R
Delwel
Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
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PJ
Valk
Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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A
Kumar
Shanghai Center for Bioinformation Technology, Shanghai, People's Republic of China.
L
L
Xie
1] Cancer Science Institute of Singapore, Singapore, Singapore [2] Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
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DG
Tenen
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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G
Huang
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
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Wang
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D018398:Homeodomain Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse