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

Haiming Xu; Daria G. Valerio; Meghan E. Eisold; Amit Sinha; Richard P. Koche; Wenhuo Hu; Chun Wei Chen; S. Haihua Chu; Gerard L. Brien; Christopher Y. Park; James J. Hsieh; Patricia Ernst; Scott A. Armstrong

doi:10.1016/j.ccell.2016.10.019

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

Haiming Xu
, Daria G. Valerio
, Meghan E. Eisold
, Amit Sinha
, Richard P. Koche
, Wenhuo Hu
, Chun Wei Chen
, S. Haihua Chu
, Gerard L. Brien
, Christopher Y. Park
, James J. Hsieh
, Patricia Ernst
, Scott A. Armstrong

Research output: Contribution to journal › Article › peer-review

142 Scopus citations

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.

Original language	English
Pages (from-to)	863-878
Number of pages	16
Journal	Cancer Cell
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.10.019
State	Published - Dec 12 2016

Keywords

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

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10.1016/j.ccell.2016.10.019

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@article{bcd63ef7177149e7971a23b799088c5b,

title = "NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis",

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",

author = "Haiming Xu and Valerio, \{Daria G.\} and Eisold, \{Meghan E.\} and Amit Sinha and Koche, \{Richard P.\} and Wenhuo Hu and Chen, \{Chun Wei\} and Chu, \{S. Haihua\} and Brien, \{Gerard L.\} and Park, \{Christopher Y.\} and Hsieh, \{James J.\} and Patricia Ernst and Armstrong, \{Scott A.\}",

note = "Funding Information: We acknowledge Alan Chramiec, Matthew Witkin, and Li Yang for assistance with the preparation of ChIP-seq libraries, and Ke Xu for assistance with the confocal microscopy. This work was supported by NIH grants PO1 CA66996 , R01 CA140575 , the Leukemia and Lymphoma Society, and Gabrielle's Angel Research Foundation (to S.A.A.); by a DoD Bone Marrow Failure Postdoctoral Fellowship award ( W81XWH-12-1-0568 ) (to H.X.); and by the Cure Childhood Cancer Foundation (to D.G.V.). S.A.A. is a consultant for Epizyme, Imago Biosciences, and Vitae Pharmaceuticals. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = dec,

day = "12",

doi = "10.1016/j.ccell.2016.10.019",

language = "English",

volume = "30",

pages = "863--878",

journal = "Cancer Cell",

issn = "1535-6108",

number = "6",

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TY - JOUR

T1 - NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis

AU - Xu, Haiming

AU - Valerio, Daria G.

AU - Eisold, Meghan E.

AU - Sinha, Amit

AU - Koche, Richard P.

AU - Hu, Wenhuo

AU - Chen, Chun Wei

AU - Chu, S. Haihua

AU - Brien, Gerard L.

AU - Park, Christopher Y.

AU - Hsieh, James J.

AU - Ernst, Patricia

AU - Armstrong, Scott A.

N1 - Funding Information: We acknowledge Alan Chramiec, Matthew Witkin, and Li Yang for assistance with the preparation of ChIP-seq libraries, and Ke Xu for assistance with the confocal microscopy. This work was supported by NIH grants PO1 CA66996 , R01 CA140575 , the Leukemia and Lymphoma Society, and Gabrielle's Angel Research Foundation (to S.A.A.); by a DoD Bone Marrow Failure Postdoctoral Fellowship award ( W81XWH-12-1-0568 ) (to H.X.); and by the Cure Childhood Cancer Foundation (to D.G.V.). S.A.A. is a consultant for Epizyme, Imago Biosciences, and Vitae Pharmaceuticals. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/12/12

Y1 - 2016/12/12

N2 - 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.

AB - 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.

KW - Hox gene

KW - NUP98 fusion

KW - leukemia

KW - mixed lineage leukemia 1

KW - non-specific lethal histone-modifying complexes

UR - https://www.scopus.com/pages/publications/85003875987

U2 - 10.1016/j.ccell.2016.10.019

DO - 10.1016/j.ccell.2016.10.019

M3 - Article

C2 - 27889185

AN - SCOPUS:85003875987

SN - 1535-6108

VL - 30

SP - 863

EP - 878

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

Keywords

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