Protein & Cell >

2021 , Vol. 12 >Issue 7: 557 - 577

DOI: https://doi.org/10.1007/s13238-020-00754-2

RESEARCH ARTICLE

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

  • Yu-Kun Xia 1,2 ,
  • Yi-Rong Zeng 1,2 ,
  • Meng-Li Zhang 1,2,3 ,
  • Peng Liu 1,2 ,
  • Fang Liu 4 ,
  • Hao Zhang 5,6 ,
  • Chen-Xi He 1 ,
  • Yi-Ping Sun 1,2 ,
  • Jin-Ye Zhang 1,2 ,
  • Cheng Zhang 1,2 ,
  • Lei Song 7,8 ,
  • Chen Ding 9 ,
  • Yu-Jie Tang 4 ,
  • Zhen Yang 1 ,
  • Chen Yang 5,6 ,
  • Pu Wang 1,2 ,
  • Kun-Liang Guan 10 ,
  • Yue Xiong 11 ,
  • Dan Ye , 1,2,12
Expand
  • 1. Huashan Hospital, Fudan University, and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, and the Shanghai Key Laboratory of Medical Epigenetics, and the Key Laboratory of Metabolism and Molecular, Ministry of Education, Shanghai 200032, China
  • 2. The International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai 200032, China
  • 3. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200032, China
  • 4. Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
  • 5. Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai 200032, China
  • 6. Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China
  • 7. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China
  • 8. National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing 102206, China
  • 9. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
  • 10. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
  • 11. Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA
  • 12. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China

Received date: 12 Apr 2020

Accepted date: 17 Jun 2020

Published date: 15 Jul 2021

Copyright

2020 The Author(s) 2020
Fold

Abstract

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Key words： ASXL1; BAP1; FOXK1/K2; leukemia; epigenetics

Cite this article

Yu-Kun Xia , Yi-Rong Zeng , Meng-Li Zhang , Peng Liu , Fang Liu , Hao Zhang , Chen-Xi He , Yi-Ping Sun , Jin-Ye Zhang , Cheng Zhang , Lei Song , Chen Ding , Yu-Jie Tang , Zhen Yang , Chen Yang , Pu Wang , Kun-Liang Guan , Yue Xiong , Dan Ye . Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network[J]. Protein & Cell, 2021 , 12(7) : 557 -577 . DOI: 10.1007/s13238-020-00754-2

References

Publishing order | Descend order by publishing year | Descend order by cited within
1
Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, Lafave LM (2013) Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med 210:2641–2659

DOI

2
Asada S, Goyama S, Inoue D, Shikata S, Takeda R, Fukushima T, Yonezawa T, Fujino T, Hayashi Y, Kawabata KC (2018) Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nat Commun 9:2733

DOI

3
Balasubramani A, Larjo A, Bassein JA, Chang X, Hastie RB, Togher SM, Lahdesmaki H, Rao A (2015) Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nat Commun 6:7307

DOI

4
Campagne A, Lee MK, Zielinski D, Michaud A, Le Corre S, Dingli F, Chen H, Shahidian LZ, Vassilev I, Servant N (2019) BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation. Nat Commun 10:348

DOI

5
Dell'Aversana C, Giorgio C, D'Amato L, Lania G, Matarese F, Saeed S, Di Costanzo A, Belsito Petrizzi V, Ingenito C, Martens JHA (2017) miR-194-5p/BCLAF1 deregulation in AML tumorigenesis. Leukemia 31:2315–2325

DOI

6
Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, Kirkpatrick DS, Pham VC, Lill JR, Bakalarski CE (2012) Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337:1541–1546

DOI

7
Duncan SA, Baganizi DR, Sahu R, Singh SR, Dennis VA (2017) SOCS proteins as regulators of inflammatory responses induced by bacterial infections: a review. Front Microbiol 8:2431

DOI

8
Fisher CL, Pineault N, Brookes C, Helgason CD, Ohta H, Bodner C, Hess JL, Humphries RK, Brock HW (2010) Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 115:38–46

DOI

9
Gao N (2005) Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation. Development 132:3431–3443

DOI

10
Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D (2012) Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol 5:12

DOI

11
Gossage L, Eisen T, Maher ER (2015) VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15:55–64

DOI

12
Heath EM, Chan SM, Minden MD, Murphy T, Shlush LI, Schimmer AD (2017) Biological and clinical consequences of NPM1 mutations in AML. Leukemia 31:798–807

DOI

13
Hsu YC, Chiu YC, Lin CC, Kuo YY, Hou HA, Tzeng YS, Kao CJ, Chuang PH, Tseng MH, Hsiao TH (2017) The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model. J Hematol Oncol 10:139

DOI

14
Inoue D, Kitaura J, Togami K, Nishimura K, Enomoto Y, Uchida T, Kagiyama Y, Kawabata KC, Nakahara F, Izawa K (2013) Myelodysplastic syndromes are induced by histone methylationaltering ASXL1 mutations. J Clin Investig 123:4627–4640

DOI

15
Inoue D, Matsumoto M, Nagase R, Saika M, Fujino T, Nakayama KI, Kitamura T (2016) Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. Exp Hematol 44:172–176.e171

DOI

16
Ji Z, Mohammed H, Webber A, Ridsdale J, Han N, Carroll JS, Sharrocks AD (2014) The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex. Nucleic Acids Res 42:6232–6242

DOI

17
Jiang M, Zhang WW, Liu P, Yu W, Liu T, Yu J (2017) Dysregulation of SOCS-mediated negative feedback of cytokine signaling in carcinogenesis and its significance in cancer treatment. Front Immunol 8:70

DOI

18
Lan F, Collins RE, De Cegli R, Alpatov R, Horton JR, Shi X, Gozani O, Cheng X, Shi Y (2007) Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448:718–722

DOI

19
Labno-Kirszniok K, Nieszporek T, Wiecek A, Helbig G, Lubinski J (2013) Acute myeloid leukemia in a 38-year-old hemodialyzed patient with von Hippel-Lindau disease. Hered Cancer Clin Pract 11:11

DOI

20
Li X, Xue Y, Liu X, Zheng J, Shen S, Yang C, Chen J, Li Z, Liu L, Ma J (2019) ZRANB2/SNHG20/FOXK1 Axis regulates Vasculogenic mimicry formation in glioma. J Exp Clin Cancer Res 38(1):68

DOI

21
Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A (2009) The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J Biol Chem 284:34179–34188

DOI

22
Micol JB, Abdel-Wahab O (2016) The role of additional sex combslike proteins in cancer. Cold Spring Harb Perspect Med 6(10):a026526

DOI

23
Moura IC, Zhang H, Song G, Song G, Li R, Gao M, Ye L, Zhang C (2018) Identification of DNA methylation prognostic signature of acute myelocytic leukemia. PLoS ONE. https://doi.org/10.1371/journal.pone.0199689

DOI

24
Nagase R, Inoue D, Pastore A, Fujino T, Hou HA, Yamasaki N, Goyama S, Saika M, Kanai A, Sera Y (2018) Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation. J Exp Med 215:1729–1747

DOI

25
Nishizawa K, Nishiyama H, Matsui Y, Kobayashi T, Saito R, Kotani H, Masutani H, Oishi S, Toda Y, Fujii N (2011) Thioredoxininteracting protein suppresses bladder carcinogenesis. Carcinogenesis 32:1459–1466

DOI

26
Sahtoe DD, van Dijk WJ, Ekkebus R, Ovaa H, Sixma TK (2016) BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nat Commun 7:10292

DOI

27
Sanchez-Pulido L, Kong L, Ponting CP (2012) A common ancestry for BAP1 and Uch37 regulators. Bioinformatics (Oxf Engl) 28:1953–1956

DOI

28
Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Muller J (2010) Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465:243–247

DOI

29
Schnittger S, Eder C, Jeromin S, Alpermann T, Fasan A, Grossmann V, Kohlmann A, Illig T, Klopp N, Wichmann HE (2013) ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 27:82–91

DOI

30
Sinclair DA, Milne TA, Hodgson JW, Shellard J, Salinas CA, Kyba M, Randazzo F, Brock HW (1998) The Additional sex combs gene of Drosophila encodes a chromatin protein that binds to shared and unique Polycomb group sites on polytene chromosomes. Development 125:1207–1216

31
Sportoletti P, Celani L, Varasano E, Rossi R, Sorcini D, Rompietti C, Strozzini F, Del Papa B, Guarente V, Spinozzi G (2019) GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations. Leukemia 33:1827–1832

DOI

32
Sukonina V, Ma H, Zhang W, Bartesaghi S, Subhash S, Heglind M, Foyn H, Betz MJ, Nilsson D, Lidell ME (2019) FOXK1 and FOXK2 regulate aerobic glycolysis. Nature 566:279–283

DOI

33
Sun T, Wang H, Li Q, Qian Z, Shen C (2016) Forkhead box protein k1 recruits TET1 to act as a tumor suppressor and is associated with MRI detection. Jpn J Clin Oncol 46:209–221

DOI

34
Thomas SJ, Snowden JA, Zeidler MP, Danson SJ (2015) The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer 113:365–371

DOI

35
Trapnell C, Pachter L, Salzberg SL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinform 25:1105–1111

DOI

36
Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, Uitterlinden AG, Erpelinck CA, Delwel R, Lowenberg B (2005) Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106:3747–3754

DOI

37
Waldhart AN, Dykstra H, Peck AS, Boguslawski EA, Madaj ZB, Wen J, Veldkamp K, Hollowell M, Zheng B, Cantley LC (2017) Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin. Cell Rep 19:2005–2013

DOI

38
White AE, Harper JW (2012) Cancer. Emerging anatomy of the BAP1 tumor suppressor system. Science 337:1463–1464

DOI

39
Williamson EA, Wolf I, O’Kelly J, Bose S, Tanosaki S, Koeffler HP (2005) BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1. Oncogene 25:1391–1399

DOI

40
Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J, Li Z, Al-Ali H, Li L, Chen Z (2018) Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood 131:328–341

DOI

41
Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J, Sui G, Hart GW, Rauscher FJ III, Drobetsky E, Milot E (2010) The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol Cell Biol 30:5071–5085

DOI

Options
Outlines

/

〈 〉