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Cancer Cell. 2016 Dec 12;30(6):863-878. doi: 10.1016/j.ccell.2016.10.019. Epub 2016 Nov 23.

NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis.

Author information

1
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: haiming_xu@dfci.harvard.edu.
2
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
5
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
6
Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: scott_armstrong@dfci.harvard.edu.

Abstract

The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions. Furthermore, MLL1 is required for the proliferation of NHA9 cells in vitro and in vivo. Inactivation of MLL1 leads to decreased expression of genes bound by NHA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukemias. Our data reveal a molecular dependency on MLL1 function in NUP98-fusion-driven leukemogenesis.

KEYWORDS:

Hox gene; NUP98 fusion; leukemia; mixed lineage leukemia 1; non-specific lethal histone-modifying complexes

PMID:
27889185
PMCID:
PMC5501282
DOI:
10.1016/j.ccell.2016.10.019
[Indexed for MEDLINE]
Free PMC Article

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