The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML.
Apoptosis
Bone Marrow
/ metabolism
Cell Differentiation
Cell Line, Tumor
Cell Membrane
/ metabolism
Drug Resistance, Neoplasm
Epigenesis, Genetic
Genotype
HEK293 Cells
HL-60 Cells
Histone Demethylases
/ antagonists & inhibitors
Histones
/ chemistry
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Leukemia, Promyelocytic, Acute
/ drug therapy
Leukocytes, Mononuclear
/ cytology
Tretinoin
/ pharmacology
p300-CBP Transcription Factors
/ metabolism
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
21
06
2019
accepted:
04
07
2019
pubmed:
3
10
2019
medline:
2
6
2020
entrez:
3
10
2019
Statut:
ppublish
Résumé
To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.
Identifiants
pubmed: 31576004
doi: 10.1038/s41375-019-0581-y
pii: 10.1038/s41375-019-0581-y
doi:
Substances chimiques
Histones
0
Tretinoin
5688UTC01R
Histone Demethylases
EC 1.14.11.-
KDM1A protein, human
EC 1.5.-
p300-CBP Transcription Factors
EC 2.3.1.48
p300-CBP-associated factor
EC 2.3.1.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2628-2639Commentaires et corrections
Type : ErratumIn
Références
Longo DL, Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136–52.
doi: 10.1056/NEJMra1406184
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21.
doi: 10.1056/NEJMoa1300874
de The H. Differentiation therapy revisited. Nat Rev Cancer. 2018;18:117–27.
doi: 10.1038/nrc.2017.103
Schenk T, Stengel S, Zelent A. Unlocking the potential of retinoic acid in anticancer therapy. Br J Cancer. 2014;111:2039–45.
doi: 10.1038/bjc.2014.412
Berglund L, Bjorling E, Oksvold P, Fagerberg L, Asplund A, Szigyarto CA, et al. A genecentric Human Protein Atlas for expression profiles based on antibodies. Mol Cell Proteom. 2008;7:2019–27.
doi: 10.1074/mcp.R800013-MCP200
Glasow A, Barrett A, Petrie K, Gupta R, Boix-Chornet M, Zhou DC, et al. DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia. Blood. 2008;111:2374–7.
doi: 10.1182/blood-2007-05-088344
Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18:605–11.
doi: 10.1038/nm.2661
Smitheman KN, Severson TM, Rajapurkar SR, McCabe MT, Karpinich N, Foley J, et al. Lysine specific demethylase 1 inactivation enhances differentiation and promotes cytotoxic response when combined with all-trans retinoic acid in acute myeloid leukemia across subtypes. Haematologica. 2018;104:1156–67.
doi: 10.3324/haematol.2018.199190
Cusan M, Cai SF, Mohammad HP, Krivtsov A, Chramiec A, Loizou E, et al. LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPalpha-dependent enhancers in AML. Blood. 2018;131:1730–42.
doi: 10.1182/blood-2017-09-807024
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473–87.
doi: 10.1016/j.ccr.2012.03.014
Mueller-Tidow C. Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible. https://ClinicalTrials.gov/show/NCT02261779 . 2014.
Ross D. IMG-7289, With and Without ATRA, in Patients With Advanced Myeloid Malignancies. https://ClinicalTrials.gov/show/NCT02842827 . 2016.
Lübbert M. Study of Sensitization of Non-M3 AML Blasts to ATRA by Epigenetic Treatment With Tranylcypromine (TCP). https://ClinicalTrials.gov/show/NCT02717884 . 2016.
Zheng F. An Open-Label, Dose-Escalation/Dose-Expansion Safety Study of INCB059872 in Subjects With Advanced Malignancies. https://ClinicalTrials.gov/show/NCT02712905 . 2016.
Watts J. Phase 1 Study of TCP-ATRA for Adult Patients With AML and MDS. https://ClinicalTrials.gov/show/NCT02273102 . 2014.
Grant PA, Eberharter A, John S, Cook RG, Turner BM, Workman JL. Expanded lysine acetylation specificity of Gcn5 in native complexes. J Biol Chem. 1999;274:5895–900.
doi: 10.1074/jbc.274.9.5895
Kuo Y-M, Andrews AJ. Quantitating the Specificity and Selectivity of Gcn5-Mediated Acetylation of Histone H3. PLoS ONE. 2013;8:e54896.
doi: 10.1371/journal.pone.0054896
Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E, Dovey OM, et al. A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia. Cell Rep. 2016;17:1193–205.
doi: 10.1016/j.celrep.2016.09.079
Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008;456:53–9.
doi: 10.1038/nature07517
Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol. 2010;28:2529–37.
doi: 10.1200/JCO.2009.23.4732
Bagger FO, Sasivarevic D, Sohi SH, Laursen LG, Pundhir S, Sonderby CK, et al. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. Nucleic Acids Res. 2016;44(D1):D917–24.
doi: 10.1093/nar/gkv1101
Biel M, Kretsovali A, Karatzali E, Papamatheakis J, Giannis A. Design, Synthesis, and Biological Evaluation of a Small‐Molecule Inhibitor of the Histone Acetyltransferase Gcn5. Angew Chem Int Ed. 2004;43:3974–6.
doi: 10.1002/anie.200453879
Dalton WT Jr., Ahearn MJ, McCredie KB, Freireich EJ, Stass SA, et al. HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3. Blood. 1988;71:242–7.
doi: 10.1182/blood.V71.1.242.242
Picot T, Aanei CM, Fayard A, Flandrin-Gresta P, Tondeur S, Gouttenoire M, et al. Expression of embryonic stem cell markers in acute myeloid leukemia. Tumour Biol. 2017;39:1010428317716629.
doi: 10.1177/1010428317716629
Xu H, Huang S, Zhu X, Zhang W, Zhang X. FOXK1 promotes glioblastoma proliferation and metastasis through activation of Snail transcription. Exp Ther Med. 2018;15:3108–16.
pubmed: 29456714
pmcid: 5795754
Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011;146:697–708.
doi: 10.1016/j.cell.2011.07.032
Rice KL, Licht JD. HOX deregulation in acute myeloid leukemia. J Clin Investig. 2007;117:865–8.
doi: 10.1172/JCI31861
Santanach A, Blanco E, Jiang H, Molloy KR, Sanso M, LaCava J, et al. The Polycomb group protein CBX6 is an essential regulator of embryonic stem cell identity. Nat Commun. 2017;8:1235.
doi: 10.1038/s41467-017-01464-w
Salvatori B, Iosue I, Mangiavacchi A, Loddo G, Padula F, Chiaretti S, et al. The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells. Cell Death Dis. 2012;3:e413.
doi: 10.1038/cddis.2012.151
Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, et al. Core circadian clock genes regulate leukemia stem cells in AML. Cell. 2016;165:303–16.
doi: 10.1016/j.cell.2016.03.015
Ramirez RN, El-Ali NC, Mager MA, Wyman D, Conesa A, Mortazavi A. Dynamic gene regulatory networks of human myeloid differentiation. Cell Syst. 2017;4:416–29. e413.
doi: 10.1016/j.cels.2017.03.005
Vegi NM, Klappacher J, Oswald F, Mulaw MA, Mandoli A, Thiel VN, et al. MEIS2 is an oncogenic partner in AML1-ETO-positive AML. Cell Rep. 2016;16:498–507.
doi: 10.1016/j.celrep.2016.05.094
Zhu J, Zhang Y, Joe GJ, Pompetti R, Emerson SG. NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci USA. 2005;102:11728–33.
doi: 10.1073/pnas.0503405102
Gal H, Amariglio N, Trakhtenbrot L, Jacob-Hirsh J, Margalit O, Avigdor A, et al. Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia. 2006;20:2147–54.
doi: 10.1038/sj.leu.2404401
Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17:1086–93.
doi: 10.1038/nm.2415
Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res. 2005;11:1372–9.
doi: 10.1158/1078-0432.CCR-04-1816
Martelli MP, Pettirossi V, Thiede C, Bonifacio E, Mezzasoma F, Cecchini D, et al. CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice. Blood. 2010;116:3907–22.
doi: 10.1182/blood-2009-08-238899
Boutzen H, Saland E, Larrue C, de Toni F, Gales L, Castelli FA, et al. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia. J Exp Med. 2016;213:483–97.
doi: 10.1084/jem.20150736
Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437:436–9.
doi: 10.1038/nature04020
Perillo B, Ombra MN, Bertoni A, Cuozzo C, Sacchetti S, Sasso A, et al. DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science. 2008;319:202–6.
doi: 10.1126/science.1147674
Bararia D, Kwok H, Welner RS, Numata A, Sárosi MB, Yang H, et al. Acetylation of C/EBPα inhibits its granulopoietic function. Nat Commun. 2016;7:10968.
doi: 10.1038/ncomms10968
Maiques-Diaz A, Spencer GJ, Lynch JT, Ciceri F, Williams EL, Amaral FMR, et al. Enhancer activation by pharmacologic displacement of lsd1 from gfi1 induces differentiation in acute myeloid leukemia. Cell Rep. 2018;22:3641–59.
doi: 10.1016/j.celrep.2018.03.012
Cain C. AML takes LSD1. Science-Business eXchange. 2012;5:352.
doi: 10.1038/scibx.2012.352
Fu X, Zhang P, Yu B. Advances toward LSD1 inhibitors for cancer therapy. Future Med Chem. 2017;9:1227–42.
doi: 10.4155/fmc-2017-0068