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Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib.
- Source :
-
International Journal of Molecular Sciences . 3/1/2019, Vol. 20 Issue 5, p1230. 1p. - Publication Year :
- 2019
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 16616596
- Volume :
- 20
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- International Journal of Molecular Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 135406231
- Full Text :
- https://doi.org/10.3390/ijms20051230