Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis.

Kojima K; Konopleva M; Tsao T; Andreeff M; Ishida H; Shiotsu Y; Jin L; Tabe Y; Nakakuma H

doi:10.1038/leu.2009.212

Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis.

Tsao T ,

Jin L ,

Tabe Y ,

Nakakuma H

Affiliations

1. Department of Hematology/Oncology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8510, Japan.
Authors
Kojima K¹
(1 author)

Leukemia, 15 Oct 2009, 24(1):33-43
https://doi.org/10.1038/leu.2009.212 PMID: 19946262

Abstract

Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.

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References

Articles referenced by this article (44)

The role of FLT3 in haematopoietic malignancies.
Stirewalt DL, Radich JP
Nat Rev Cancer, (9):650-665 2003
MED: 12951584
Internal tandem duplication of the flt3 gene found in acute myeloid leukemia.
Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S
Leukemia, (12):1911-1918 1996
MED: 8946930
Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T
Blood, (8):2434-2439 2001
MED: 11290608
Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis.
Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T
Leukemia, (8):1345-1349 2005
MED: 15959528
FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications.
Whitman SP, Ruppert AS, Radmacher MD, Mrozek K, Paschka P, Langer C, Baldus CD, Wen J, Racke F, Powell BL, Kolitz JE, Larson RA, Caligiuri MA, Marcucci G, Bloomfield CD
Blood, (3):1552-1559 2007
MED: 17940205
Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations.
Radomska HS, Basseres DS, Zheng R, Zhang P, Dayaram T, Yamamoto Y, Sternberg DW, Lokker N, Giese NA, Bohlander SK, Schnittger S, Delmotte MH, Davis RJ, Small D, Hiddemann W, Gilliland DG, Tenen DG
J Exp Med, (2):371-381 2006
MED: 16446383
Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.
Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H
Blood, (12):3907-3914 2000
MED: 11090077
Activation mechanisms of STAT5 by oncogenic Flt3-ITD.
Choudhary C, Brandts C, Schwable J, Tickenbrock L, Sargin B, Ueker A, Bohmer FD, Berdel WE, Muller-Tidow C, Serve H
Blood, (1):370-374 2007
MED: 17356133
Rsk1 mediates a MEK-MAP kinase cell survival signal.
Shimamura A, Ballif BA, Richards SA, Blenis J
Curr Biol, (3):127-135 2000
MED: 10679322
Title not supplied
AUTHOR UNKNOWN

Show 10 more references (10 of 44)

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