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Volume 20
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10.3390/ijms20051230
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Article

Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib

by
Ya-Chen Ko
1,†,
Chung-Yi Hu
2,3,†,
Zheng-Hau Liu
2,
Hwei-Fang Tien
4,
Da-Liang Ou
5,
Hsiung-Fei Chien
6,7,* and
Liang-In Lin
2,3,*
1
Department of Medical Imaging and Radiological Technology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
2
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
3
Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
4
Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
5
Department of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
6
Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan
7
TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 110, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(5), 1230; https://doi.org/10.3390/ijms20051230
Received: 31 January 2019 / Revised: 2 March 2019 / Accepted: 6 March 2019 / Published: 11 March 2019
(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)
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Abstract

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML. View Full-Text
Keywords: cytarabine; acute myeloid leukemia; drug-resistance; FLT3-ITD cytarabine; acute myeloid leukemia; drug-resistance; FLT3-ITD
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MDPI and ACS Style

Ko, Y.-C.; Hu, C.-Y.; Liu, Z.-H.; Tien, H.-F.; Ou, D.-L.; Chien, H.-F.; Lin, L.-I. Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib. Int. J. Mol. Sci. 2019, 20, 1230. https://doi.org/10.3390/ijms20051230

AMA Style

Ko Y-C, Hu C-Y, Liu Z-H, Tien H-F, Ou D-L, Chien H-F, Lin L-I. Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib. International Journal of Molecular Sciences. 2019; 20(5):1230. https://doi.org/10.3390/ijms20051230

Chicago/Turabian Style

Ko, Ya-Chen, Chung-Yi Hu, Zheng-Hau Liu, Hwei-Fang Tien, Da-Liang Ou, Hsiung-Fei Chien, and Liang-In Lin. 2019. "Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib" International Journal of Molecular Sciences 20, no. 5: 1230. https://doi.org/10.3390/ijms20051230

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