ETV6/FLT3 Fusion Is a Novel Client Protein of Hsp90

Overview

Journal Oncol Res

Specialty Oncology

Date 2018 Feb 24

PMID 29471895

Citations 3

Authors

Bui Thi Kim Ly

Hoang Thanh Chi

Affiliations

Soon will be listed here.

Abstract

FMS-like tyrosine kinase-3 fragments from exon 14 to the end without any mutations or deletions have been reported to fuse to ETV6 (TEL) in a few cases of myeloid/lymphoid neoplasms with eosinophilia carrying a translocation t(12;13)(p13;q12). This fusion protein confers constitutive activation on the FLT3 fragment and induces factor-independent growth in transfected Ba/F3 cells, indicating that it is an oncoprotein. However, the mechanism controlling the stability of this oncoprotein is unknown. In this study, we focus on finding factors controlling the stability of ETV6/FLT3. We have shown that the stability of ETV6/FLT3 is regulated by the Hsp90 chaperone. ETV6/FLT3 fusion protein forms a complex with Hsp90 by coimmunoprecipitation analyses using an Hsp90 antibody. The association between ETV6/FLT3 fusion protein and Hsp90 was impaired after treating ETV6/FLT3 transient transfection cos7 cells with 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG induced a time- and dose-dependent downregulation of ectopically expressed ETV6/FLT3 protein in cos7 and HeLa-transfected cells. By using cycloheximide to block new protein translation, we found that 17-AAG accelerated the decay of ETV6/FLT3. Our findings could contribute to more understanding of the ETV6/FLT3 regulation through Hsp90 chaperone and open the way to finding effective treatment strategies for this rare disease.

Citing Articles

Native and tagged CENP-A histones are functionally inequivalent.

Bui M, Baek S, Bentahar R, Melters D, Dalal Y Epigenetics Chromatin. 2024; 17(1):19.

PMID: 38825690 PMC: 11145777. DOI: 10.1186/s13072-024-00543-9.

Small Molecule Induced FLT3 Degradation.

Han S Pharmaceuticals (Basel). 2022; 15(3).

PMID: 35337118 PMC: 8954439. DOI: 10.3390/ph15030320.

Sorafenib Induced Complete Cytogenetic and Molecular Response in a Chronic Eosinophilic Leukemia Case with t(12;13) Translocation.

Ricci F, Balducci S, Guerrini F, Grassi S, Ciabatti E, Barate C Clin Hematol Int. 2021; 2(3):129-131.

PMID: 34595453 PMC: 8432331. DOI: 10.2991/chi.k.200714.001.

References

Stirewalt D, Radich J . The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003; 3(9):650-65. DOI: 10.1038/nrc1169. View

Chonabayashi K, Hishizawa M, Kawamata S, Nagai Y, Ohno T, Ishikawa T . Direct binding of Grb2 has an important role in the development of myeloproliferative disease induced by ETV6/FLT3. Leukemia. 2012; 27(6):1433-6. DOI: 10.1038/leu.2012.333. View

Oshikawa G, Nagao T, Wu N, Kurosu T, Miura O . c-Cbl and Cbl-b ligases mediate 17-allylaminodemethoxygeldanamycin-induced degradation of autophosphorylated Flt3 kinase with internal tandem duplication through the ubiquitin proteasome pathway. J Biol Chem. 2011; 286(35):30263-30273. PMC: 3162385. DOI: 10.1074/jbc.M111.232348. View

Yao Q, Nishiuchi R, Li Q, Kumar A, Hudson W, Kersey J . FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases. Clin Cancer Res. 2003; 9(12):4483-93. View

Minami Y, Kiyoi H, Yamamoto Y, Yamamoto K, Ueda R, Saito H . Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia. 2002; 16(8):1535-40. DOI: 10.1038/sj.leu.2402558. View

Walz C, Erben P, Ritter M, Bloor A, Metzgeroth G, Telford N . Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. Blood. 2011; 118(8):2239-42. DOI: 10.1182/blood-2011-03-343426. View

Tse K, Mukherjee G, Small D . Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia. 2000; 14(10):1766-76. DOI: 10.1038/sj.leu.2401905. View

Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover K, Karras G . Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell. 2012; 150(5):987-1001. PMC: 3894786. DOI: 10.1016/j.cell.2012.06.047. View

Chonabayashi K, Hishizawa M, Matsui M, Kondo T, Ohno T, Ishikawa T . Successful allogeneic stem cell transplantation with long-term remission of ETV6/FLT3-positive myeloid/lymphoid neoplasm with eosinophilia. Ann Hematol. 2013; 93(3):535-7. DOI: 10.1007/s00277-013-1843-9. View

10.

Vu H, Xinh P, Masuda M, Motoji T, Toyoda A, Sakaki Y . FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation. Leukemia. 2006; 20(8):1414-21. DOI: 10.1038/sj.leu.2404266. View

11.

Vu H, Xinh P, Kano Y, Tokunaga K, Sato Y . The juxtamembrane domain in ETV6/FLT3 is critical for PIM-1 up-regulation and cell proliferation. Biochem Biophys Res Commun. 2009; 383(3):308-13. DOI: 10.1016/j.bbrc.2009.03.157. View

12.

Ly B, Chi H, Yamagishi M, Kano Y, Hara Y, Nakano K . Inhibition of FLT3 expression by green tea catechins in FLT3 mutated-AML cells. PLoS One. 2013; 8(6):e66378. PMC: 3688791. DOI: 10.1371/journal.pone.0066378. View