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Acute Leukemias

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

Leukemia volume 28, pages 1436–1448 (2014)Cite this article

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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.

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Acknowledgements

We thank Drs Jose Cancelas, H Leighton Grimes, James Mulloy, Susumu Goyama (Cincinnati Children’s Hospital Medical Center) and Frank Rosenbauer (Max Delbrück Center for Molecular Medicine) for their critical reading and valuable comments on the manuscript. We also thank Tami R Bartell for English editing. This study was supported by the Hundred Talents Program of the Chinese Academy of Sciences (to QFW), the National Natural Science Foundation of China grants No. 81070442 and No. 91331111 (to QFW), No. 81100381 (to JZ), No. 81300438 (to JW) and the ‘Strategic Priority Research Program’ of the Chinese Academy of Sciences (to QFW), No. XDA01010305. This work was also supported in part by the Knowledge Innovation Program of the Chinese Academy of Sciences (to FHH) and sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (to QFW). We would like to acknowledge support from the Cincinnati Children’s Hospital Research Foundation, the Ohio Cancer Research Associates, the Cancer Free Kids, the Leukemia Research Foundation and the Pilot Research Grant of the State Key Laboratory of Experimental Hematology (Tianjin, China) (to GH), the NIH grant HL112719 (to DGT) and NIH grant HL111192 (to AK).

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  1. J Zhou, J Wu and B Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China

    J Zhou, J Wu, B Li, D Liu, S Zheng, J Wang, L Zhang, L Zhang, F He, Q Li, A Chen, X Zhao, J Yan & Q-f Wang

  2. University of Chinese Academy of Sciences, Beijing, People's Republic of China

    B Li, D Liu, S Zheng, L Zhang & A Chen

  3. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    B Li, X Yan, A Chen, Y Zhang, X Zhao & G Huang

  4. Shanghai Center for Bioinformation Technology, Shanghai, People's Republic of China

    J Yu & L Xie

  5. Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA

    J Wang

  6. Respiratory Department, 2nd Branch of First Hospital of Jilin University, Changchun, People's Republic of China

    Y Guan

  7. Tongji Medical College of Huazhong University of Science & Technology, Wuhan, People's Republic of China

    J Ni

  8. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    M A Nobrega

  9. Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands

    B Löwenberg, R Delwel & P J M Valk

  10. Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    A Kumar

  11. Cancer Science Institute of Singapore, Singapore, Singapore

    D G Tenen

  12. Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA

    D G Tenen

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Zhou, J., Wu, J., Li, B. et al. PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway. Leukemia 28, 1436–1448 (2014). https://doi.org/10.1038/leu.2013.384

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