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Spreafico M, Gruszka AM, Valli D, et al. HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia. Front Cell Dev Biol. 2020;8:844doi: 10.3389/fcell.2020.00844.
Spreafico, M., Gruszka, A. M., Valli, D., Mazzola, M., Deflorian, G., Quintè, A., Totaro, M. G., Battaglia, C., Alcalay, M., Marozzi, A., & Pistocchi, A. (2020). HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia. Frontiers in cell and developmental biology, 8844. https://doi.org/10.3389/fcell.2020.00844
Spreafico, Marco, et al. "HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia." Frontiers in cell and developmental biology vol. 8 (2020): 844. doi: https://doi.org/10.3389/fcell.2020.00844
Spreafico M, Gruszka AM, Valli D, Mazzola M, Deflorian G, Quintè A, Totaro MG, Battaglia C, Alcalay M, Marozzi A, Pistocchi A. HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia. Front Cell Dev Biol. 2020 Sep 04;8:844. doi: 10.3389/fcell.2020.00844. eCollection 2020. PMID: 33015043; PMCID: PMC7498549.
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Front Cell Dev Biol. 2020 Sep 04;8:844. doi: 10.3389/fcell.2020.00844. eCollection 2020.

HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia.

Frontiers in cell and developmental biology

Marco Spreafico, Alicja M Gruszka, Debora Valli, Mara Mazzola, Gianluca Deflorian, Arianna Quintè, Maria Grazia Totaro, Cristina Battaglia, Myriam Alcalay, Anna Marozzi, Anna Pistocchi

Affiliations

  1. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
  2. Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia IRCCS, Milan, Italy.
  3. Cogentech, Società Benefit, Milan, Italy.
  4. Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.

PMID: 33015043 PMCID: PMC7498549 DOI: 10.3389/fcell.2020.00844

Abstract

Histone deacetylase 8 (HDAC8), a class I HDAC that modifies non-histone proteins such as p53, is highly expressed in different hematological neoplasms including a subtype of acute myeloid leukemia (AML) bearing inversion of chromosome 16 [inv(16)]. To investigate HDAC8 contribution to hematopoietic stem cell maintenance and myeloid leukemic transformation, we generated a zebrafish model with Hdac8 overexpression and observed an increase in hematopoietic stem/progenitor cells, a phenotype that could be reverted using a specific HDAC8 inhibitor, PCI-34051 (PCI). In addition, we demonstrated that AML cell lines respond differently to PCI treatment: HDAC8 inhibition elicits cytotoxic effect with cell cycle arrest followed by apoptosis in THP-1 cells, and cytostatic effect in HL60 cells that lack p53. A combination of cytarabine, a standard anti-AML chemotherapeutic, with PCI resulted in a synergistic effect in all the cell lines tested. We, then, searched for a mechanism behind cell cycle arrest caused by HDAC8 inhibition in the absence of functional p53 and demonstrated an involvement of the canonical WNT signaling in zebrafish and in cell lines. Together, we provide the evidence for the role of HDAC8 in hematopoietic stem cell differentiation in zebrafish and AML cell lines, suggesting HDAC8 inhibition as a therapeutic target in hematological malignancies. Accordingly, we demonstrated the utility of a highly specific HDAC8 inhibition as a therapeutic strategy in combination with standard chemotherapy.

Copyright © 2020 Spreafico, Gruszka, Valli, Mazzola, Deflorian, Quintè, Totaro, Battaglia, Alcalay, Marozzi and Pistocchi.

Keywords: AML; HDAC8; PCI-34051; WNT; p53; zebrafish

References

  1. Blood. 2020 Apr 23;135(17):1472-1483 - PubMed
  2. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):407-12 - PubMed
  3. Hum Mol Genet. 2019 Jan 1;28(1):64-73 - PubMed
  4. Crit Rev Oncol Hematol. 2017 Jul;115:13-22 - PubMed
  5. Dig Dis Sci. 2013 Dec;58(12):3545-53 - PubMed
  6. Cell Stem Cell. 2009 Jan 9;4(1):37-48 - PubMed
  7. Blood. 2012 Aug 23;120(8):1601-12 - PubMed
  8. Dev Dyn. 1995 Jul;203(3):253-310 - PubMed
  9. FEBS Lett. 2000 Jul 28;478(1-2):77-83 - PubMed
  10. Oncotarget. 2017 May 19;8(31):51429-51446 - PubMed
  11. Mol Cell Biol. 2004 Jan;24(2):765-73 - PubMed
  12. Oncol Rep. 2011 Jun;25(6):1677-81 - PubMed
  13. Dev Biol. 2002 Jan 15;241(2):229-37 - PubMed
  14. Blood. 2005 Dec 1;106(12):3803-10 - PubMed
  15. Cell Death Dis. 2015 Feb 19;6:e1657 - PubMed
  16. J Clin Oncol. 2012 Jun 20;30(18):2204-10 - PubMed
  17. Proc Natl Acad Sci U S A. 1985 Feb;82(3):790-4 - PubMed
  18. Clin Cancer Res. 2009 Jan 1;15(1):91-9 - PubMed
  19. Cell Stem Cell. 2015 Nov 5;17(5):597-610 - PubMed
  20. Curr Opin Hematol. 2002 Jul;9(4):322-32 - PubMed
  21. Blood Cancer J. 2012 May;2(5):e69 - PubMed
  22. Cancer Sci. 2016 Nov;107(11):1543-1549 - PubMed
  23. Cancers (Basel). 2016 Aug 20;8(8): - PubMed
  24. Mol Cell Biol. 2003 Jan;23(2):607-19 - PubMed
  25. J Biol Chem. 2000 May 19;275(20):15254-64 - PubMed
  26. Cells. 2019 Nov 07;8(11): - PubMed
  27. Structure. 2004 Jul;12(7):1325-34 - PubMed
  28. J Cell Physiol. 2011 Sep;226(9):2215-21 - PubMed
  29. Haematologica. 2019 Jul;104(7):1332-1341 - PubMed
  30. Blood. 2011 Jul 14;118(2):289-97 - PubMed
  31. Crit Rev Biochem Mol Biol. 2017 Aug;52(4):414-424 - PubMed
  32. Biochem J. 2000 Aug 15;350 Pt 1:199-205 - PubMed
  33. Nature. 2012 Sep 13;489(7415):313-7 - PubMed
  34. Eur J Cancer. 2009 May;45(7):1137-1145 - PubMed
  35. Epigenetics. 2014 Nov;9(11):1511-20 - PubMed
  36. Cell Signal. 2016 May;28(5):506-515 - PubMed
  37. Clin Epigenetics. 2011 Aug;2(2):389-99 - PubMed
  38. Cell Cycle. 2012 Sep 1;11(17):3219-26 - PubMed
  39. N Engl J Med. 2015 Sep 17;373(12):1136-52 - PubMed
  40. Br J Cancer. 2016 Mar 15;114(6):605-11 - PubMed
  41. J Cell Physiol. 2019 May;234(5):6067-6076 - PubMed
  42. Histopathology. 2009 May;54(6):688-98 - PubMed
  43. Oncol Rep. 2007 Oct;18(4):769-74 - PubMed
  44. Cancer Res. 2015 Nov 15;75(22):4803-16 - PubMed
  45. MethodsX. 2018 Oct 10;5:1287-1290 - PubMed
  46. Pharmacol Res Perspect. 2015 Jun;3(3):e00149 - PubMed
  47. Blood. 2017 Dec 14;130(24):2619-2630 - PubMed
  48. Ann Hematol. 2017 Nov;96(11):1825-1832 - PubMed
  49. Br J Haematol. 2009 Nov;147(4):515-25 - PubMed
  50. Pediatr Blood Cancer. 2012 Dec 15;59(7):1245-51 - PubMed
  51. Pharmaceuticals (Basel). 2010 Aug 26;3(9):2751-2767 - PubMed
  52. ACS Chem Biol. 2014 Oct 17;9(10):2210-6 - PubMed
  53. Am J Physiol Cell Physiol. 2014 Aug 1;307(3):C288-95 - PubMed
  54. Blood. 2013 May 2;121(18):3640-9 - PubMed
  55. Leukemia. 2005 Oct;19(10):1751-9 - PubMed
  56. Int J Mol Sci. 2017 Jul 01;18(7): - PubMed
  57. Br J Haematol. 2010 Sep;150(6):665-73 - PubMed
  58. Leukemia. 2008 May;22(5):1026-34 - PubMed
  59. Nature. 2012 Jan 11;481(7380):157-63 - PubMed

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