Blockade of Mitogen-activated Protein Kinase/extracellular Signal-regulated Kinase Kinase and Murine Double Minute Synergistically Induces Apoptosis in Acute Myeloid Leukemia Via BH3-only Proteins Puma and Bim

Overview

Journal Cancer Res

Specialty Oncology

Date 2010 Mar 11

PMID 20215498

Citations 43

Authors

Weiguo Zhang

Marina Konopleva

Jared K Burks

Karen C Dywer

Wendy D Schober

Jer-Yen Yang

Teresa J McQueen

Mien-Chie Hung

Michael Andreeff

Affiliations

Soon will be listed here.

Abstract

Molecular aberrations of the Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK and/or Murine double minute (MDM2)/p53 signaling pathways have been reported in 80% and 50% of primary acute myeloid leukemia (AML) samples and confer poor outcome. In this study, antileukemic effects of combined MEK inhibition by AZD6244 and nongenotoxic p53 activation by MDM2 antagonist Nutlin-3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin-3a triggered synergistic proapoptotic responses in AML cell lines [combination index (CI) = 0.06 +/- 0.03 and 0.43 +/- 0.03 in OCI/AML3 and MOLM13 cells, respectively] and in primary AML cells (CI = 0.52 +/- 0.01). Mechanistically, the combination upregulated levels of BH3-only proteins Puma and Bim, in part via transcriptional upregulation of the FOXO3a transcription factor. Suppression of Puma and Bim by short interfering RNA rescued OCI/AML3 cells from AZD/Nutlin-induced apoptosis. These results strongly indicate the therapeutic potential of combined MEK/MDM2 blockade in AML and implicate Puma and Bim as major regulators of AML cell survival.

Citing Articles

Proteomic Comparison of Acute Myeloid Leukemia Cells and Normal CD34 Bone Marrow Cells: Studies of Leukemia Cell Differentiation and Regulation of Iron Metabolism/Ferroptosis.

Selheim F, Aasebo E, Reikvam H, Bruserud O, Hernandez-Valladares M Proteomes. 2025; 13(1).

PMID: 39982321 PMC: 11843884. DOI: 10.3390/proteomes13010011.

From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.

Ahmadi S, Rahimian E, Rahimi S, Zarandi B, Bahraini M, Soleymani M Biomark Res. 2024; 12(1):137.

PMID: 39538363 PMC: 11565275. DOI: 10.1186/s40364-024-00676-9.

Biomarkers of Response to Venetoclax Therapy in Acute Myeloid Leukemia.

Rodriguez-Medina C, Stuckey R, Bilbao-Sieyro C, Gomez-Casares M Int J Mol Sci. 2024; 25(3).

PMID: 38338698 PMC: 10855565. DOI: 10.3390/ijms25031421.

Small-molecule correctors and stabilizers to target p53.

Fallatah M, Law F, Chow W, Kaiser P Trends Pharmacol Sci. 2023; 44(5):274-289.

PMID: 36964053 PMC: 10511064. DOI: 10.1016/j.tips.2023.02.007.

WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia.

Zhu Y, Tong X, Wang Y, Lu X Cell Death Dis. 2021; 13(1):18.

PMID: 34930905 PMC: 8688515. DOI: 10.1038/s41419-021-04467-0.

References

Clodi K, Kliche K, Zhao S, Weidner D, Schenk T, Consoli U . Cell-surface exposure of phosphatidylserine correlates with the stage of fludarabine-induced apoptosis in chronic lymphocytic leukemia and expression of apoptosis-regulating genes. Cytometry. 2000; 40(1):19-25. DOI: 10.1002/(sici)1097-0320(20000501)40:1<19::aid-cyto3>3.0.co;2-3. View

Akgul C . Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2008; 66(8):1326-36. PMC: 11131550. DOI: 10.1007/s00018-008-8637-6. View

Moye P, Blalock W, Hoyle P, Chang F, Franklin R, Weinstein-Oppenheimer C . Synergy between Raf and BCL2 in abrogating the cytokine dependency of hematopoietic cells. Leukemia. 2000; 14(6):1060-79. DOI: 10.1038/sj.leu.2401792. View

Blalock W, Moye P, Chang F, Pearce M, Steelman L, McMahon M . Combined effects of aberrant MEK1 activity and BCL2 overexpression on relieving the cytokine dependency of human and murine hematopoietic cells. Leukemia. 2000; 14(6):1080-96. DOI: 10.1038/sj.leu.2401793. View

Dijkers P, Medema R, Lammers J, Koenderman L, Coffer P . Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 2000; 10(19):1201-4. DOI: 10.1016/s0960-9822(00)00728-4. View

Dijkers P, Medema R, Pals C, Banerji L, Thomas N, Lam E . Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol. 2000; 20(24):9138-48. PMC: 102172. DOI: 10.1128/MCB.20.24.9138-9148.2000. View

Yu J, Zhang L, Hwang P, Kinzler K, Vogelstein B . PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell. 2001; 7(3):673-82. DOI: 10.1016/s1097-2765(01)00213-1. View

Milella M, Kornblau S, Estrov Z, Carter B, Lapillonne H, Harris D . Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest. 2001; 108(6):851-9. PMC: 200930. DOI: 10.1172/JCI12807. View

Gartel A, Tyner A . The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther. 2002; 1(8):639-49. View

10.

Weston C, Balmanno K, Chalmers C, Hadfield K, Molton S, Ley R . Activation of ERK1/2 by deltaRaf-1:ER* represses Bim expression independently of the JNK or PI3K pathways. Oncogene. 2003; 22(9):1281-93. DOI: 10.1038/sj.onc.1206261. View

11.

Tran H, Brunet A, Griffith E, Greenberg M . The many forks in FOXO's road. Sci STKE. 2003; 2003(172):RE5. DOI: 10.1126/stke.2003.172.re5. View

12.

Ley R, Balmanno K, Hadfield K, Weston C, Cook S . Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem. 2003; 278(21):18811-6. DOI: 10.1074/jbc.M301010200. View

13.

Gilley J, Coffer P, Ham J . FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol. 2003; 162(4):613-22. PMC: 2173804. DOI: 10.1083/jcb.200303026. View

14.

Lunghi P, Tabilio A, DallAglio P, Ridolo E, Carlo-Stella C, Pelicci P . Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia. 2003; 17(9):1783-93. DOI: 10.1038/sj.leu.2403032. View

15.

Kerr A, James J, Smith M, Willson C, Court E, Smith J . An investigation of the MEK/ERK inhibitor U0126 in acute myeloid leukemia. Ann N Y Acad Sci. 2004; 1010:86-9. DOI: 10.1196/annals.1299.013. View

16.

Johnson D, Schneider-Broussard R . Role of E2F in cell cycle control and cancer. Front Biosci. 1998; 3:d447-8. DOI: 10.2741/a291. View

17.

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

18.

Vogelstein B, Kinzler K . p53 function and dysfunction. Cell. 1992; 70(4):523-6. DOI: 10.1016/0092-8674(92)90421-8. View

19.

Milne D, Campbell D, Caudwell F, Meek D . Phosphorylation of the tumor suppressor protein p53 by mitogen-activated protein kinases. J Biol Chem. 1994; 269(12):9253-60. View

20.

Seliger B, Papadileris S, Vogel D, Hess G, Brendel C, Storkel S . Analysis of the p53 and MDM-2 gene in acute myeloid leukemia. Eur J Haematol. 1996; 57(3):230-40. DOI: 10.1111/j.1600-0609.1996.tb01369.x. View