Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML.
Acetanilides
/ pharmacology
Animals
Apoptosis
/ drug effects
CRISPR-Cas Systems
Cell Nucleus
/ drug effects
Drug Synergism
Heterocyclic Compounds, 3-Ring
/ pharmacology
Humans
Leukemia, Myeloid, Acute
/ complications
Mice
Mice, Inbred NOD
Mice, SCID
Myeloproliferative Disorders
/ complications
Nitriles
Protein Kinase Inhibitors
/ pharmacology
Pyrazoles
/ pharmacology
Pyrimidines
Signal Transduction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
beta Catenin
/ antagonists & inhibitors
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
07
08
2018
accepted:
16
10
2018
revised:
23
09
2018
pubmed:
24
12
2018
medline:
7
9
2019
entrez:
22
12
2018
Statut:
ppublish
Résumé
Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.
Identifiants
pubmed: 30575820
doi: 10.1038/s41375-018-0334-3
pii: 10.1038/s41375-018-0334-3
doi:
Substances chimiques
Acetanilides
0
Heterocyclic Compounds, 3-Ring
0
Nitriles
0
OTX015
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Pyrimidines
0
beta Catenin
0
ruxolitinib
82S8X8XX8H
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1373-1386Subventions
Organisme : NCI NIH HHS
ID : R01 CA173877
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197589
Pays : United States
Références
Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129:667–79.
pubmed: 28028029
Rampal R, Al-Shahrour F, Abdel-Wahab O, Patel JP, Brunel JP, Mermel CH, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014;123:e123–33.
pubmed: 24740812
pmcid: 4041169
Kleppe M, Kwak M, Koppikar P, Riester M, Keller M, Bastian L, et al. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov. 2015;5:316–31.
pubmed: 25572172
pmcid: 4355105
Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol. 2014;21:65–71.
pubmed: 24366192
Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci USA. 2014;111:E5401–10.
pubmed: 25516983
Zhang SJ, Rampal R, Manshouri T, Patel J, Mensah N, Kayserian A, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood. 2012;119:4480–5.
pubmed: 22431577
pmcid: 3362363
Spiegel JY, McNamara C, Kennedy JA, Panzarella T, Arruda A, Stockley T, et al. Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy. Blood Adv. 2017;1:1729–38.
pubmed: 29296819
pmcid: 5728340
Leroy E, Constantinescu SN. Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile janus kinase inhibition. Leukemia. 2017;31:1023–38.
pubmed: 28119526
Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100:1139–45.
pubmed: 26069290
pmcid: 4800694
Bose P, Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood. 2017;130:115–25.
pubmed: 28500170
pmcid: 5510786
Kundranda MN, Tibes R, Mesa RA. Transformation of a chronic myeloproliferative neoplasm to acute myelogenous leukemia: does anything work? Curr Hematol Malig Rep. 2012;7:78–86.
pubmed: 22170483
Verstovsek S, Fiskus W, Manshouri T, Bhalla KN. Targeting cistrome and dysregulated transcriptome of post-MPN sAML. Oncotarget. 2017;8:93301–2.
pubmed: 29212143
pmcid: 5706789
Fiskus W, Verstovsek S, Manshouri T, Rao R, Balusu R, Venkannagari S, et al. Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells. Clin Cancer Res. 2011;17:7347–58.
pubmed: 21976548
pmcid: 3743080
Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489:155–9.
pubmed: 22820254
pmcid: 3991463
Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res. 2014;20:2051–9.
pubmed: 24583800
pmcid: 3990645
Akahane K, Sanda T, Mansour MR, Radimerski T, DeAngelo DJ, Weinstock DM, et al. HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia. Leukemia. 2016;30:219–28.
pubmed: 26265185
Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.
pubmed: 22682243
Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327:1650–3.
pubmed: 20339075
pmcid: 3084586
Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D, et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell. 2010;18:606–18.
pubmed: 21156284
Petropoulos K, Arseni N, Schessl C, Stadler CR, Rawat VP, Deshpande AJ, et al. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med. 2008;205:515–22.
pubmed: 18316418
pmcid: 2275375
Mosimann C, Hausmann G, Basler K. Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol. 2009;10:276–86.
pubmed: 19305417
Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.
pubmed: 28575679
Liu YC, Lai WC, Chuang KA, Shen YJ, Hu WS, Ho CH, et al. Blockade of JAK2 activity suppressed accumulation of beta-catenin in leukemic cells. J Cell Biochem. 2010;111:402–11.
pubmed: 20503246
Li J, Wang CY. TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol. 2008;10:160–9.
pubmed: 18193033
Oberoi J, Fairall L, Watson PJ, Yang JC, Czimmerer Z, Kampmann T, et al. Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery. Nat Struct Mol Biol. 2011;18:177–84.
pubmed: 21240272
pmcid: 3232451
Dimitrova YN, Li J, Lee YT, Rios-Esteves J, Friedman DB, Choi HJ, et al. Direct ubiquitination of beta-catenin by Siah-1 and regulation by the exchange factor TBL1. J Biol Chem. 2010;285:13507–16.
pubmed: 20181957
pmcid: 2859511
Li JY, Daniels G, Wang J, Zhang X. TBL1XR1 in physiological and pathological states. Am J Clin Exp Urol. 2015;3:13–23.
pubmed: 26069883
pmcid: 4446378
Fiskus W, Sharma S, Saha S, Shah B, Devaraj SG, Sun B, et al. Pre-clinical efficacy of combined therapy with novel beta-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia. 2015;29:1267–78.
pubmed: 25482131
Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31:1951–61.
pubmed: 28042144
pmcid: 5537055
Wan L, Wen H, Li Y, Lyu J, Xi Y, Hoshii T, et al. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature. 2017;543:265–9.
pubmed: 28241141
pmcid: 5372383
Ramasamy K, Khatun H, Macpherson L, Caley MP, Sturge J, Mufti GJ, et al. Fluorescence-based experimental model to evaluate the concomitant effect of drugs on the tumour microenvironment and cancer cells. Br J Haematol. 2012;157:564–79.
pubmed: 22428569
Fisher DAC, Malkova O, Engle EK, Miner CA, Fulbright MC, Behbehani GK, et al. Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia. 2017;31:1962–74.
pubmed: 28008177
Fiskus W, Verstovsek S, Manshouri T, Smith JE, Peth K, Abhyankar S, et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 2013;12:577–88.
pubmed: 23445613
Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell. 2015;28:15–28.
pubmed: 26175413
pmcid: 4503933
Li L, Sheng Y, Li W, Hu C, Mittal N, Tohyama K, et al. beta-Catenin is a candidate therapeutic target for myeloid neoplasms with del(5q). Cancer Res. 2017;77:4116–26.
pubmed: 28611040
pmcid: 5559383
Barbieri E, Deflorian G, Pezzimenti F, Valli D, Saia M, Meani N, et al. Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development. Oncotarget. 2016;7:55302–12.
pubmed: 27486814
pmcid: 5342418
Dietrich PA, Yang C, Leung HH, Lynch JR, Gonzales E, Liu B, et al. GPR84 sustains aberrant beta-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. Blood. 2014;124:3284–94.
pubmed: 25293777
Kajiguchi T, Chung EJ, Lee S, Stine A, Kiyoi H, Naoe T, et al. FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia. 2007;21:2476–84.
pubmed: 17851558
Kajiguchi T, Katsumi A, Tanizaki R, Kiyoi H, Naoe T. Y654 of beta-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of beta-catenin. Eur J Haematol. 2012;88:314–20.
pubmed: 22126602
Coluccia AM, Vacca A, Dunach M, Mologni L, Redaelli S, Bustos VH, et al. Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 2007;26:1456–66.
pubmed: 17318191
pmcid: 1817619
Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature. 2014;506:240–4.
pubmed: 24429522
pmcid: 4116754
Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13:513–32.
pubmed: 24981364
pmcid: 4426976
Kim YM, Gang EJ, Kahn M. CBP/catenin antagonists: targeting LSCs’ Achilles heel. Exp Hematol. 2017;52:1–11.
pubmed: 28479420
pmcid: 5526056
Soldi R, Horrigan SK, Cholody MW, Padia J, Sorna V, Bearss J, et al. Design, synthesis, and biological evaluation of a series of anthracene-9,10-dione dioxime beta-catenin pathway inhibitors. J Med Chem. 2015;58:5854–62.
pubmed: 26182238
Savvidou I, Khong T, Cuddihy A, McLean C, Horrigan S, Spencer A. Beta-catenin inhibitor BC2059 is efficacious as monotherapy or in combination with proteasome inhibitor bortezomib in multiple myeloma. Mol Cancer Ther. 2017;16:1765–78.
pubmed: 28500235
Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328–33.
pubmed: 24522528
pmcid: 4991939
Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.
pubmed: 27926740
Bhagwat N, Koppikar P, Keller M, Marubayashi S, Shank K, Rampal R, et al. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014;123:2075–83.
pubmed: 24470592
pmcid: 3968390
Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell. 2017;168:629–43.
pubmed: 28187285
pmcid: 5308559
Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54:728–36.
pubmed: 24905006
Wyspianska BS, Bannister AJ, Barbieri I, Nangalia J, Godfrey A, Calero-Nieto FJ, et al. BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. Leukemia. 2014;28:88–97.
pubmed: 23929215
Saenz DT, Fiskus W, Manshouri T, Rajapakshe K, Krieger S, Sun B, et al. BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells. Leukemia. 2017;31:678–87.
pubmed: 27677740
Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem. 2016;55:1966–73.
Fong CY, Gilan O, Lam EY, Rubin AF, Ftouni S, Tyler D, et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature. 2015;525:538–42.
pubmed: 26367796
pmcid: 6069604
Rathert P, Roth M, Neumann T, Muerdter F, Roe JS, Muhar M, et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015;525:543–7.
pubmed: 26367798
pmcid: 4921058