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Pivot Concepts:
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Target Concepts:
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Query: UNIPROT:P31749 (
AKT
)
22,954
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As
2
O
3
) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. The combination of FLT3 TKIs with ATO showed synergistic effects in reducing proliferation, viability and colony forming ability, and increased apoptosis in FLT3/ITD+ cells and primary patient samples. In contrast, no cooperativity was observed against wild-type FLT3 leukemia cells. ATO reduced expression of FLT3 RNA and its upstream transcriptional regulators (HOXA9, MEIS1), and induced poly-ubiquitination and degradation of the
FLT3 protein
, partly through reducing its binding with USP10. ATO also synergizes with FLT3 TKIs to inactivate FLT3 autophosphorylation and phosphorylation of its downstream signaling targets, including STAT5,
AKT
and ERK. Furthermore, ATO combined with sorafenib, a FLT3 TKI,
in vivo
reduced growth of FLT3/ITD+ leukemia cells in NSG recipients. In conclusion, these results suggest that ATO is a potential candidate to study in clinical trials in combination with FLT3 TKIs to improve the treatment of FLT3/ITD+ leukemia.
...
PMID:Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3. 3025 Jun 37
Objective:
To summarize the abnormal location of FLT3 caused by different glycosylation status which further leads to the distinguishing signaling pathways and discuss targeting on FLT3 glycosylation by drugs reported in recent literatures.
Methods:
We review FLT3 glycosylation in endoplasmic reticulum. The abnormal signal of mutant FLT3 with different glycosylation status is discussed. We also address potential FLT3 glycosylation-targeting strategies for the treatment.
Results:
Inhibition of FLT3 mutant cells by drugs reported in recent literatures involves the influence of glycosylation of FLT3: 2-deoxy-D-glucose, Tunicamycin and Fluvastatin are reported to inhibit N-glycosylation of FLT3; Pim-1 inhibitors are proved to block the inhibition of Pim-1 on FLT3 Oglycosylation; HSP90 inhibitors and Tyrosine Kinase Inhibitors are shown to increase fully glycosylated form of FLT3.
Discussion:
The FMS-like tyrosine kinase 3 (FLT3) gene expressed only in CD34+ progenitor cells in bone marrow is located on chromosome 13q12 encoding
FLT3 protein
. FLT3 is initially synthesized as a 110 KD protein, which glycosylated in the endoplasmic reticulum to a 130 KD immature protein rich in mannose, and further processed into a mature 160 KD protein in the Golgi apparatus, which could be transferred to the cell surface. Therapy targeting on FLT3 glycosylation is a promising direction for AML treatment.
Conclusions:
The abnormal location of FLT3 caused by different glycosylation status leads to the distinguishing signaling pathways. Targeting on FLT3 glycosylation may provide a new perspective for therapeutic strategies.
Abbreviations:
ABCG2: ATP-binding cassette transporter breast cancer resistance protein; ATF: activating transcription factor; AML: acute myeloid leukemia; CHOP: CCAAT-enhancer-binding protein homologous protein; 2-DG: 2-deoxy-D-glucose; EFS: event free survival; EPO: erythropoietin; EPOR: erythropoietin receptor; ERS: endoplasmic reticulum stress; FLT3: FMS-like tyrosine kinase 3; GPI: glycosylphosphatidylinositol; HSP: heat shock protein; ITD: internal tandem duplication; IRE1a: inositol-requiring enzyme 1 alpha; JNK: c-Jun N-terminal kinase; JMD: juxtamembrane domain; JAK: janus kinase; MAPK/ERK: mitogen activated protein kinase/extracellular signal-regulated protein kinase; OS: overall survival; PI3K/
AKT
: phosphatidylinositide 3-kinases/protein kinase B; PERK: RNA-activated protein kinase-like endoplasmic reticulum kinase; Pgp: P-glycoprotein; PTX3: human pentraxin-3; STAT: signal transducer and activator of transcriptions; TKD: tyrosine-kinase domain; TKI: tyrosine kinase inhibitor; TM: Tunicamycin; UPR: unfolded protein reaction.
...
PMID:Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia. 3153 45
