HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia

Ganqian Zhu; Huacheng Luo; Yang Feng; Olga A Guryanova; Jianfeng Xu; Shi Chen; Qian Lai; Arati Sharma; Bing Xu; Zhigang Zhao; Ru Feng; Hongyu Ni; David Claxton; Ying Guo; Ruben A Mesa; Yi Qiu; Feng-Chun Yang; Wei Li; Stephen D Nimer; Suming Huang; Mingjiang Xu

doi:10.1038/s41467-021-22095-2

HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia

Nat Commun. 2021 Mar 29;12(1):1956. doi: 10.1038/s41467-021-22095-2.

Authors

Ganqian Zhu^#^{1

2}, Huacheng Luo^#³, Yang Feng⁴, Olga A Guryanova⁴, Jianfeng Xu⁵, Shi Chen^{1

2}, Qian Lai³, Arati Sharma⁶, Bing Xu⁷, Zhigang Zhao⁸, Ru Feng⁹, Hongyu Ni¹⁰, David Claxton^{6

11}, Ying Guo^{2

12}, Ruben A Mesa^{13

14}, Yi Qiu^{11

15}, Feng-Chun Yang^{2

12

14

16}, Wei Li¹⁷, Stephen D Nimer^{16

18}, Suming Huang^{19

20}, Mingjiang Xu^{21

22

23

24}

Affiliations

¹ Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
² Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
³ Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
⁴ Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, USA.
⁵ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
⁶ Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
⁷ Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, 361026, Fujian, China.
⁸ Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
⁹ Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
¹⁰ Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
¹¹ Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
¹² Department of Cell System & Anatomy, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
¹³ Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
¹⁴ Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
¹⁵ Department of Cellular & Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
¹⁶ Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
¹⁷ Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA.
¹⁸ Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
¹⁹ Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. shuang4@pennstatehealth.psu.edu.
²⁰ Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. shuang4@pennstatehealth.psu.edu.
²¹ Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. xum1@uthscsa.edu.
²² Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. xum1@uthscsa.edu.
²³ Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. xum1@uthscsa.edu.
²⁴ Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. xum1@uthscsa.edu.

^# Contributed equally.

Abstract

Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c⁺). NPM1c⁺ maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c⁺ controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c⁺-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c⁺-driven leukemogenesis by rectifying the signature of NPM1c⁺ leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1^c/+) mice. HoxBlincTg and Npm1^c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c⁺ signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c⁺ leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c⁺ AML.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinogenesis / genetics*
Carcinogenesis / metabolism
Carcinogenesis / pathology
Cell Line, Tumor
Cell Proliferation
Gene Expression Profiling
Gene Expression Regulation, Leukemic*
Heterografts
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism
Histones / genetics
Histones / metabolism
Homeodomain Proteins / genetics*
Homeodomain Proteins / metabolism
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Mice
Mice, Transgenic
Multigene Family
Mutation
Myeloid Ecotropic Viral Integration Site 1 Protein / genetics
Myeloid Ecotropic Viral Integration Site 1 Protein / metabolism
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism
Myelopoiesis / genetics
Nuclear Proteins / deficiency
Nuclear Proteins / genetics*
Nucleophosmin
Promoter Regions, Genetic
RNA, Long Noncoding / agonists
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
Signal Transduction
Transcription, Genetic

Substances

Histones
Homeodomain Proteins
KMT2A protein, human
MEIS1 protein, human
Myeloid Ecotropic Viral Integration Site 1 Protein
NPM1 protein, human
Npm1 protein, mouse
Nuclear Proteins
RNA, Long Noncoding
histone H3 trimethyl Lys4
Nucleophosmin
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase

Abstract

Publication types

MeSH terms

Substances

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