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.
Highlights
Acute myeloid leukemia (AML) is a disorder of clonal hyperproliferation of abnormal myeloid progenitor cells emerging from a heterogeneous genetic background
Analysis of surface marker expression by flow cytometry showed no gross changes in the profile of CD markers, except an increase in CD56 (22.6% to 37.0%) and CD16 (5.7% to 8.8%) as well as a decrease in HLA-DR (12.7% to 2.4%) in MV4-11-R compared to MV4-11-P
Cell proliferation curves and cytarabine cytotoxicities were assessed over a two-year period; the phenotypes and the IC50 values of cytarabine of the resistant cell line remained stable over time
Summary
Acute myeloid leukemia (AML) is a disorder of clonal hyperproliferation of abnormal myeloid progenitor cells emerging from a heterogeneous genetic background. Patients are given a consolidation therapy involving a high dose of cytarabine. Among the 50–75% of those who achieve complete remission after induction therapy, 80% suffer disease relapse attributed to drug resistance [1,2]. Cytarabine resistance in AML cells was shown to be linked to aberrant expression of equilibrative nucleoside transporters (ENT1) and metabolic enzymes deoxycytidine kinase (DCK) and cytosolic 5 -nucleotidase-II (NT5C2) [3,4,5]. Enhanced drug export activities of multidrug resistance proteins were reported to be linked to AML chemoresistance [6,7]. The sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) was shown to hydrolyze the active metabolite of cytarabine, cytarabine triphosphate (ara-CTP), and be involved in cytarabine resistance of AML cells [12,13]
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