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International Journal of Hematology
Published in: International Journal of Hematology 1/2019

01-01-2019 | Progress in Hematology

Targeting transcription factors in acute myeloid leukemia

Authors: Hisashi Takei, Susumu S. Kobayashi

Published in: International Journal of Hematology | Issue 1/2019

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Abstract

Transcription factors recognize and bind to consensus sequence elements that are specific for each transcription factor, and the transcription factors then regulate downstream gene expression. In the bone marrow, transcription factors, such as C/EBPα, PU.1, and RUNX1, control essential genes to maintain the normal hematopoietic system. Dysregulation of transcription factors caused by gene mutations, chromosomal aberrations, or aberrant expression can lead to cancer, including acute myeloid leukemia. In the past, transcription factors were not considered “druggable” targets. However, a better understanding of the pathology of malignant tumors and mechanisms of transcriptional regulation has enabled us to develop novel therapeutic strategies that target transcription factors. In this review, we focus on transcription factors that play important roles in leukemogenesis and current efforts and prospects in the development of transcriptional therapy. We believe that such a therapeutic approach will benefit patients with cancers that involve acute myeloid leukemia in the near future.
Literature
1.
Pulte D, Gondos A, Brenner H. Expected long-term survival of patients diagnosed with acute myeloblastic leukemia during 2006–2010. Ann Oncol. 2010;21:335–41.CrossRefPubMed
2.
Lourenco AR, Coffer PJ. A tumor suppressor role for C/EBPalpha in solid tumors: more than fat and blood. Oncogene. 2017;36:5221–30.CrossRefPubMed
3.
Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol. 1994;14:5558–68.CrossRefPubMedPubMedCentral
4.
Seipel K, Marques MT, Bozzini MA, Meinken C, Mueller BU, Pabst T. Inactivation of the p53-KLF4-CEBPA axis in acute myeloid leukemia. Clin Cancer Res. 2016;22:746–56.CrossRefPubMed
5.
Suh HC, Gooya J, Renn K, Friedman AD, Johnson PF, Keller JR. C/EBPalpha determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood. 2006;107:4308–16.CrossRefPubMedPubMedCentral
6.
Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK, et al. Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood. 2002;100:483–90.CrossRefPubMed
7.
8.
Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001;27:263–70.CrossRefPubMed
9.
10.
Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, et al. BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet. 2002;30:48–58.CrossRefPubMed
11.
Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001;7:444–51.CrossRefPubMed
12.
Namasu CY, Katzerke C, Brauer-Hartmann D, Wurm AA, Gerloff D, Hartmann JU, et al. ABR, a novel inducer of transcription factor C/EBPalpha, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia. Oncotarget. 2017;8:103626–39.CrossRefPubMedPubMedCentral
13.
Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha N-terminal leukemia. Nat Chem Biol. 2015;11:571–8.CrossRefPubMedPubMedCentral
14.
Zheng L, Wang L, Gan J, Zhang H. RNA activation: promise as a new weapon against cancer. Cancer Lett. 2014;355:18–24.CrossRefPubMed
15.
Reebye V, Saetrom P, Mintz PJ, Huang KW, Swiderski P, Peng L, et al. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology. 2014;59:216–27.CrossRefPubMed
16.
Radomska HS, Jernigan F, Nakayama S, Jorge SE, Sun L, Tenen DG, et al. A cell-based high-throughput screening for inducers of myeloid differentiation. J Biomol Screen. 2015;20:1150–9.CrossRefPubMedPubMedCentral
17.
Zhang P, Zhang X, Iwama A, Yu C, Smith KA, Mueller BU, et al. PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood. 2000;96:2641–8.PubMed
18.
Antony-Debre I, Paul A, Leite J, Mitchell K, Kim HM, Carvajal LA, et al. Pharmacological inhibition of the transcription factor PU.1 in leukemia. J Clin Invest. 2017;127:4297–313CrossRefPubMedPubMedCentral
19.
Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004;36:624–30.CrossRefPubMed
20.
Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005;106:1590–600.CrossRefPubMedPubMedCentral
21.
Morita K, Suzuki K, Maeda S, Matsuo A, Mitsuda Y, Tokushige C, et al. Genetic regulation of the RUNX transcription factor family has antitumor effects. J Clin Invest. 2017;127:2815–28.CrossRefPubMedPubMedCentral
22.
Guo H, Ma O, Speck NA, Friedman AD. Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood. 2012;119:4408–18.CrossRefPubMedPubMedCentral
23.
Huang G, Zhang P, Hirai H, Elf S, Yan X, Chen Z, et al. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat Genet. 2008;40:51–60.CrossRefPubMed
24.
Chuang LS, Ito K, Ito Y. RUNX family: Regulation and diversification of roles through interacting proteins. Int J Cancer. 2013;132:1260–71.CrossRefPubMed
25.
Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9:862–73.CrossRefPubMed
26.
Chen F, Wang W, El-Deiry WS. Current strategies to target p53 in cancer. Biochem Pharmacol. 2010;80:724–30.CrossRefPubMed
27.
Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, et al. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 2014;74:5855–65.CrossRefPubMedPubMedCentral
28.
Zhao Y, Aguilar A, Bernard D, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J Med Chem. 2015;58:1038–52.CrossRefPubMed
29.
Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014;57:1454–72.CrossRefPubMed
30.
Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014;13:217–36.CrossRefPubMed
31.
32.
33.
Tan A, Bitterman P, Sonenberg N, Peterson M, Polunovsky V. Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1. Oncogene. 2000;19:1437–47.CrossRefPubMed
34.
Eischen CM, Packham G, Nip J, Fee BE, Hiebert SW, Zambetti GP, et al. Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1. Oncogene. 2001;20:6983–93.CrossRefPubMed
35.
Yin X, Giap C, Lazo JS, Prochownik EV. Low molecular weight inhibitors of Myc–Max interaction and function. Oncogene. 2003;22:6151–9.CrossRefPubMed
36.
37.
Savino M, Annibali D, Carucci N, Favuzzi E, Cole MD, Evan GI, et al. The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. PLoS One. 2011;6:e22284.CrossRefPubMedPubMedCentral
38.
Brondfield S, Umesh S, Corella A, Zuber J, Rappaport AR, Gaillard C, et al. Direct and indirect targeting of MYC to treat acute myeloid leukemia. Cancer Chemother Pharmacol. 2015;76:35–46.CrossRefPubMedPubMedCentral
39.
40.
Uttarkar S, Dasse E, Coulibaly A, Steinmann S, Jakobs A, Schomburg C, et al. Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction. Blood. 2016;127:1173–82.CrossRefPubMed
41.
Walf-Vorderwulbecke V, Pearce K, Brooks T, Hubank M, van den Heuvel-Eibrink MM, Zwaan CM, et al. Targeting acute myeloid leukemia by drug-induced c-MYB degradation. Leukemia. 2017;32:882–889.CrossRefPubMed
42.
Uttarkar S, Piontek T, Dukare S, Schomburg C, Schlenke P, Berdel WE, et al. Small-molecule disruption of the Myb/p300 cooperation targets acute myeloid leukemia cells. Mol Cancer Ther. 2016;15:2905–15.CrossRefPubMed
43.
Hellsten R, Johansson M, Dahlman A, Dizeyi N, Sterner O, Bjartell A. Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3. Prostate. 2008;68:269–80.CrossRefPubMed
44.
45.
Don-Doncow N, Escobar Z, Johansson M, Kjellstrom S, Garcia V, Munoz E, et al. Galiellalactone is a direct inhibitor of the transcription factor STAT3 in prostate cancer cells. J Biol Chem. 2014;289:15969–78.CrossRefPubMedPubMedCentral
46.
Cercek A, Wheler J, Murray PE, Zhou S, Saltz L. Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors. Invest New Drugs. 2015;33:1086–92.CrossRefPubMed
47.
Sakamoto KM, Grant S, Saleiro D, Crispino JD, Hijiya N, Giles F, et al. Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab. 2015;114:397–402.CrossRefPubMed
48.
Mitton B, Chae HD, Hsu K, Dutta R, Aldana-Masangkay G, Ferrari R, et al. Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells. Leukemia. 2016;30:2302–11.CrossRefPubMedPubMedCentral
49.
Mitton B, Hsu K, Dutta R, Tiu BC, Cox N, McLure KG, et al. Small molecule screen for inhibitors of expression from canonical CREB response element-containing promoters. Oncotarget. 2016;7:8653–62.CrossRefPubMedPubMedCentral
50.
Peng H, Wang H, Xue P, Hou Y, Dong J, Zhou T, et al. Suppression of NRF2-ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells. Toxicol Appl Pharmacol. 2016;292:1–7.CrossRefPubMed
51.
Karathedath S, Rajamani BM, Musheer Aalam SM, Abraham A, Varatharajan S, Krishnamurthy P, et al. Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2. PLoS One. 2017;12:e0177227.CrossRefPubMedPubMedCentral
Metadata
Title
Targeting transcription factors in acute myeloid leukemia
Authors
Hisashi Takei
Susumu S. Kobayashi
Publication date
01-01-2019
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 1/2019
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-018-2488-1

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