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Spotlight on Epigenetics and Hematologic Malignancies

The ASXL–BAP1 axis: new factors in myelopoiesis, cancer and epigenetics

Leukemia volume 27, pages 10–15 (2013)Cite this article

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Abstract

The recent identification of germline and somatic mutations in BAP1 as well as in multiple members of the ASXL (additional sex combs-like) family of genes has highlighted the role of these proteins in a diverse array of biological functions. A diverse number of possible functions have previously been ascribed to ASXL1 in non-hematopoietic contexts, including physical co-operativity with HP1a and LSD1. Here we discuss new evidence for a BAP1-independent function of ASXL1 in regulating histone H3 lysine 27 methylation through interactions with the Polycomb-repressive complex 2 (PRC2). BAP1, a nuclear-localized deubiquitinase, has been shown to interact with a number of proteins, including ASXL1 and/or ASXL2, but the functional importance of this interaction has remained elusive. Here, we highlight recent work revealing the critical function of BAP1 in restricting myelopoiesis and in regulating hematopoietic stem cell function. These data provide evidence that BAP1 and ASXL1 function as a novel class of tumor suppressors in myeloid malignancies. BAP1 functions through effects on stability of host cell factor-1, and O-GlcNAcylation, and ASXL1 impacts histone post-translational modifications through interaction with PRC2. Future studies investigating the mechanism of transformation by loss of BAP1 and ASXL1 may result in new therapeutic approaches to treat hematological malignancies.

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References

  1. Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 2012; 337: 1541–1546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abdel-Wahab O, Adli M, Lafave LM, Gao J, Hricik T, Shih AH et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 2012; 22: 180–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sowa ME, Bennett EJ, Gygi SP, Harper JW . Defining the human deubiquitinating enzyme interaction landscape. Cell 2009; 138: 389–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sinclair DA, Milne TA, Hodgson JW, Shellard J, Salinas CA, Kyba M et al. The additional sex combs gene of Drosophila encodes a chromatin protein that binds to shared and unique Polycomb group sites on polytene chromosomes. Development 1998; 125: 1207–1216.

    CAS  PubMed  Google Scholar 

  6. Park UH, Yoon SK, Park T, Kim EJ, Um SJ . Additional sex comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor {gamma}. J Biol Chem 2011; 286: 1354–1363.

    Article  CAS  PubMed  Google Scholar 

  7. Lee SW, Cho YS, Na JM, Park UH, Kang M, Kim EJ et al. ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1. J Biol Chem 2010; 285: 18–29.

    Article  CAS  PubMed  Google Scholar 

  8. Cho YS, Kim EJ, Park UH, Sin HS, Um SJ . Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor. J Biol Chem 2006; 281: 17588–17598.

    Article  CAS  PubMed  Google Scholar 

  9. Fisher CL, Pineault N, Brookes C, Helgason CD, Ohta H, Bodner C et al. Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 2010; 115: 38–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Aravind L, Iyer LM . The HARE-HTH and associated domains: novel modules in the coordination of epigenetic DNA and protein modifications. Cell Cycle 2012; 11: 119–131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Metzeler KH, Becker H, Maharry K, Radmacher MD, Kohlschmidt J, Mrozek K et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 2011; 118: 6920–6929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia 2011; 25: 1200–1202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J et al. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol 2011; 29: 2499–2506.

    Article  CAS  PubMed  Google Scholar 

  16. Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ et al. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia 2010; 24: 1062–1065.

    Article  CAS  PubMed  Google Scholar 

  17. Gelsi-Boyer V, Trouplin V, Adelaide J, Bonansea J, Cervera N, Carbuccia N et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145: 788–800.

    Article  CAS  PubMed  Google Scholar 

  18. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 2010; 465: 243–247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 2008; 32: 491–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 2008; 32: 503–518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 1998; 16: 1097–1112.

    Article  CAS  PubMed  Google Scholar 

  22. Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG et al. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res 2008; 68: 6953–6962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kovacs G, Erlandsson R, Boldog F, Ingvarsson S, Muller-Brechlin R, Klein G et al. Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma. Proc Natl Acad Sci USA 1988; 85: 1571–1575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330: 1410–1413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 2011; 48: 856–859.

    Article  CAS  PubMed  Google Scholar 

  26. Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 2011; 43: 668–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 2011; 43: 1022–1025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 2011; 43: 1018–1021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 2012; 44: 17–19.

    Article  CAS  Google Scholar 

  30. Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A, Wang S et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012; 44: 751–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL, Shao J et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 2012; 44: 53–57.

    Article  CAS  Google Scholar 

  32. Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J, Sui G et al. 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 2010; 30: 5071–5085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hoischen A, van Bon BW, Rodriguez-Santiago B, Gilissen C, Vissers LE, de Vries P et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet 2011; 43: 729–731.

    Article  CAS  PubMed  Google Scholar 

  34. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J et al. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol 2009; 29: 2181–2192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Eletr ZM, Wilkinson KD . An emerging model for BAP1’s role in regulating cell cycle progression. Cell Biochem Biophys 2011; 60: 3–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Capotosti F, Guernier S, Lammers F, Waridel P, Cai Y, Jin J et al. O-GlcNAc transferase catalyzes site-specific proteolysis of HCF-1. Cell 2011; 144: 376–388.

    Article  CAS  PubMed  Google Scholar 

  38. Knez J, Piluso D, Bilan P, Capone JP . Host cell factor-1 and E2F4 interact via multiple determinants in each protein. Mol Cell Biochem 2006; 288: 79–90.

    Article  CAS  PubMed  Google Scholar 

  39. Tyagi S, Chabes AL, Wysocka J, Herr W . E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol Cell 2007; 27: 107–119.

    Article  CAS  PubMed  Google Scholar 

  40. Hanover JA, Krause MW, Love DC . Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol 2012; 13: 312–321.

    Article  CAS  PubMed  Google Scholar 

  41. Baskind HA, Na L, Ma Q, Patel MP, Geenen DL, Wang QT . Functional conservation of Asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene Asx. PLoS One 2009; 4: e4750.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adelaide J, Rey J et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009; 23: 2183–2186.

    Article  CAS  PubMed  Google Scholar 

  43. Guglielmelli P, Biamonte F, Score J, Hidalgo-Curtis C, Cervantes F, Maffioli M et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood 2011; 118: 5227–5234.

    Article  CAS  PubMed  Google Scholar 

  44. Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 2010; 70: 447–452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314: 268–274.

    Article  PubMed  Google Scholar 

  46. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008; 455: 1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    O Abdel-Wahab

  2. Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA

    A Dey

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Correspondence to O Abdel-Wahab or A Dey.

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Abdel-Wahab, O., Dey, A. The ASXL–BAP1 axis: new factors in myelopoiesis, cancer and epigenetics. Leukemia 27, 10–15 (2013). https://doi.org/10.1038/leu.2012.288

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