Drugging the Unfolded Protein Response in Acute Leukemias

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2015 Jul 17

PMID 26179601

Citations 17

Authors

Behzad Kharabi Masouleh

Eric Chevet

Jens Panse

Edgar Jost

Michael ODwyer

Tim H Bruemmendorf

Afshin Samali

Affiliations

Soon will be listed here.

Abstract

The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.

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References

Brodsky J, Skach W . Protein folding and quality control in the endoplasmic reticulum: Recent lessons from yeast and mammalian cell systems. Curr Opin Cell Biol. 2011; 23(4):464-75. PMC: 3154734. DOI: 10.1016/j.ceb.2011.05.004. View

Miller G, Bruno B, Lim C . Resistant mutations in CML and Ph(+)ALL - role of ponatinib. Biologics. 2014; 8:243-54. PMC: 4208348. DOI: 10.2147/BTT.S50734. View

Gorman A, Healy S, Jager R, Samali A . Stress management at the ER: regulators of ER stress-induced apoptosis. Pharmacol Ther. 2012; 134(3):306-16. DOI: 10.1016/j.pharmthera.2012.02.003. View

Erba H . Finding the optimal combination therapy for the treatment of newly diagnosed AML in older patients unfit for intensive therapy. Leuk Res. 2015; 39(2):183-91. DOI: 10.1016/j.leukres.2014.11.027. View

Wang J, Dick J . Cancer stem cells: lessons from leukemia. Trends Cell Biol. 2005; 15(9):494-501. DOI: 10.1016/j.tcb.2005.07.004. View

Carlini L, Manley S . Live intracellular super-resolution imaging using site-specific stains. ACS Chem Biol. 2013; 8(12):2643-8. DOI: 10.1021/cb400467x. View

Dengler M, Staiger A, Gutekunst M, Hofmann U, Doszczak M, Scheurich P . Oncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis. PLoS One. 2011; 6(9):e25139. PMC: 3176818. DOI: 10.1371/journal.pone.0025139. View

Sakamoto K, Grant S, Saleiro D, Crispino J, Hijiya N, Giles F . Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab. 2014; 114(3):397-402. PMC: 4355162. DOI: 10.1016/j.ymgme.2014.11.017. View

Schultz K, Bowman W, Aledo A, Slayton W, Sather H, Devidas M . Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009; 27(31):5175-81. PMC: 2773475. DOI: 10.1200/JCO.2008.21.2514. View

10.

DiNardo C, Cortes J . New treatment for acute myelogenous leukemia. Expert Opin Pharmacother. 2014; 16(1):95-106. DOI: 10.1517/14656566.2015.981527. View

11.

Burnett A, Hills R, Milligan D, Goldstone A, Prentice A, McMullin M . Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol. 2009; 28(4):586-95. DOI: 10.1200/JCO.2009.22.9088. View

12.

Greim H, Kaden D, Larson R, Palermo C, Rice J, Ross D . The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. Ann N Y Acad Sci. 2014; 1310:7-31. PMC: 4002179. DOI: 10.1111/nyas.12362. View

13.

Li Y, Guo Y, Tang J, Jiang J, Chen Z . New insights into the roles of CHOP-induced apoptosis in ER stress. Acta Biochim Biophys Sin (Shanghai). 2014; 46(8):629-40. DOI: 10.1093/abbs/gmu048. View

14.

de Boer J, Walf-Vorderwulbecke V, Williams O . In focus: MLL-rearranged leukemia. Leukemia. 2013; 27(6):1224-8. DOI: 10.1038/leu.2013.78. View

15.

McCubrey J, Steelman L, Kempf C, Chappell W, Abrams S, Stivala F . Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol. 2011; 226(11):2762-81. DOI: 10.1002/jcp.22647. View

16.

Bertolotti A, Zhang Y, Hendershot L, Harding H, Ron D . Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000; 2(6):326-32. DOI: 10.1038/35014014. View

17.

Ermakova S, Kang B, Choi B, Choi H, Schuster T, Ma W . (-)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res. 2006; 66(18):9260-9. DOI: 10.1158/0008-5472.CAN-06-1586. View

18.

Kriss C, Pinilla-Ibarz J, Mailloux A, Powers J, Tang C, Kang C . Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood. 2012; 120(5):1027-38. PMC: 3680046. DOI: 10.1182/blood-2011-11-394346. View

19.

Roboz G . Current treatment of acute myeloid leukemia. Curr Opin Oncol. 2012; 24(6):711-9. DOI: 10.1097/CCO.0b013e328358f62d. View

20.

Coltella N, Percio S, Valsecchi R, Cuttano R, Guarnerio J, Ponzoni M . HIF factors cooperate with PML-RARα to promote acute promyelocytic leukemia progression and relapse. EMBO Mol Med. 2014; 6(5):640-50. PMC: 4023886. DOI: 10.1002/emmm.201303065. View