FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression

Gui-lan, Jin; Matsushita, Hiromichi; Asai, Satoshi; Tsukamoto, Hideo; Ono, Ryoichi; Nosaka, Tetsuya; Yahata, Takashi; Takahashi, Shinichiro; Miyachi, Hayato

doi:10.1016/j.bbrc.2009.10.094

Cited by 36 publications

(35 citation statements)

References 29 publications

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“…32 In vitro evidence suggests that FLT3-ITD may contribute to drug resistance. FLT3-ITD-expressing murine and human myeloid cell lines are resistant to cytosine arabinoside (ara-C), an essential agent in AML chemotherapy regimens, and both cell lines have downregulated equilibrative nucleoside transporter 1 (ENT1), a protein responsible for the cellular uptake of ara-C. 38 Decreased levels of ENT1 may be related to the upregulation of hypoxiainducible factor 1 a subunit observed in these cells. Hypoxiainducible factor 1 a subunit is known to downregulate the promoter activity of the ENT1 gene.…”

Section: Flt3 As a Prognostic Markermentioning

confidence: 99%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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Section: Flt3 As a Prognostic Markermentioning

confidence: 99%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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“…There is evidence in support of mutant FLT3 itself contributing to resistance of AML to chemotherapeutic agents. For instance, in a study in which FLT3-ITD was introduced into myeloid cell lines, FLT3-ITD expression was observed to correlate with Ara-c resistance due to decreased cellular uptake of Ara-c (Jin et al, 2009). Drug resistance was accompanied by downregulation of a transporter responsible for Ara-C cellular uptake, equilibrative nucleoside transporter 1 (ENT1), possibly mediated by upregulation of hypoxia-inducible factor 1 alpha subunit (HIF1A) (Jin et al, 2009).…”

Section: Pgpmentioning

confidence: 99%

“…For instance, in a study in which FLT3-ITD was introduced into myeloid cell lines, FLT3-ITD expression was observed to correlate with Ara-c resistance due to decreased cellular uptake of Ara-c (Jin et al, 2009). Drug resistance was accompanied by downregulation of a transporter responsible for Ara-C cellular uptake, equilibrative nucleoside transporter 1 (ENT1), possibly mediated by upregulation of hypoxia-inducible factor 1 alpha subunit (HIF1A) (Jin et al, 2009). Pretreatment with PKC412 reversed the reduced cellular uptake of Ara-c in FLT3-ITD-expressing myeloid cells (Jin et al, 2009).…”

Section: Pgpmentioning

confidence: 99%

“…Drug resistance was accompanied by downregulation of a transporter responsible for Ara-C cellular uptake, equilibrative nucleoside transporter 1 (ENT1), possibly mediated by upregulation of hypoxia-inducible factor 1 alpha subunit (HIF1A) (Jin et al, 2009). Pretreatment with PKC412 reversed the reduced cellular uptake of Ara-c in FLT3-ITD-expressing myeloid cells (Jin et al, 2009).…”

Section: Pgpmentioning

confidence: 99%

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Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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“…Additionally, DNA repair contributes to the FLT3-ITD drug-resistant phenotype of primary AML (17). Several studies demonstrate drug resistance conferred by FLT3-ITD (16,18,19); however, thus far, no studies have demonstrated the effect of mutations in the FLT3 TKD on anticancer drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Internal tandem duplication and tyrosine kinase domain mutations in FLT3 alter the response to daunorubicin in Ba/F3 cells

Takahashi

Shirahama

2015

Biomedical Reports

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Abstract. Internal tandem duplication (ITD) and activating point mutations, mainly at aspartic acid 835 in the tyrosine kinase domain (TKD), are frequently identified in the Fms-related tyrosine kinase 3 (FLT3) receptor gene in acute myeloid leukemia. The ITD in FLT3 (FLT3-ITD) confers resistance to several chemotherapeutic drugs; however, the relative effects of FLT3-ITD and FLT3-TKD mutations on the efficacy of these drugs have not been reported. In the present study, ITD or TKD mutant forms of FLT3 in Ba/F3 cells were expressed, as in the absence of interleukin-3 (IL-3) the growth of these cells is completely dependent on FLT3 oncogenic signals. As a result, the 50% effective dose for daunorubicin was significantly higher in both Ba/F3-FLT3-ITD clones, and also in one of the two Ba/F3-FLT3-TKD clones when cells were cultured without IL-3. This phenomenon was not observed for cytarabine in either Ba/F3-FLT3-ITD or Ba/F3-FLT3-TKD cells. Collectively, these results indicate that ITD and TKD mutations in FLT3 may confer daunorubicin resistance in Ba/F3 cells.

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FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression

Cited by 36 publications

References 29 publications

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Drug resistance in mutant FLT3-positive AML

Internal tandem duplication and tyrosine kinase domain mutations in FLT3 alter the response to daunorubicin in Ba/F3 cells

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