GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells

Zhang, Beibei; Ayuda‐Durán, Pilar; Piechaczyk, Laure; Fløisand, Yngvar; Safont, Mireia Mayoral; Karlsen, Ida Tveit; Fandalyuk, Zina; Tadele, Dagim Shiferaw; Mierlo, Pepijn van; Rowe, Alexander D.; Robertson, Joseph; Gjertsen, Bjørn Tore; McCormack, Emmet; Enserink, Jorrit M.

doi:10.3324/haematol.2019.220533

Cited by 7 publications

(8 citation statements)

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“…Aberrantly activated FLT3-kinase is considered to represent an attractive therapeutic target in AML. Several tyrosine kinase inhibitors (TKIs) are in development as targeted therapy for FLT3 mutant AML [38]. Sorafenib (first generation of TKIs) has been shown to improve EFS, but not OS in younger adults with AML; Midostaurin (first generation of TKIs) improves OS with a HR of 0.78 [39].…”

Section: Prognosis and Current Treatments Of Mutant Flt3 In Patientsmentioning

confidence: 99%

“…Though adding FLT3 inhibitors to standard frontline chemotherapy in FLT3 mutant AML patients results in a survival benefit [37], unfortunately, FLT3-ITD TKIs only have a relatively modest and transient effect, indicating that TKIs do not completely eradicate LSCs. TKI resistance can occur as a result of mutations in the kinase domain of FLT3 [38]. The treatment needs to be improved urgently.…”

Section: Prognosis and Current Treatments Of Mutant Flt3 In Patientsmentioning

confidence: 99%

“…Zhang et al [38] believe that oncoproteins cause UPR, while UPR causes HSP90 activation to stabilize oncoproteins and form positive feedback to cause cancer progression (Figure 2).…”

Section: Abnormal Signal Of Mutant Flt3 With Different Glycosylation mentioning

confidence: 99%

“…HSP90 combines with FLT3-ITD to stabilize its structure, which makes FLT3-ITD accumulate abnormally in the endoplasmic reticulum [94]. FLT3-ITD activates UPR to increase the expression of HSP90 which in turn stabilizes FLT3-ITD + proteins to protect acute myeloid leukemia cells from apoptosis [38]. HSP90 protects oncoproteins from misfolding and degradation.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

“…Failure of FLT3-ITD to translocate to the cell surface is accompanied by a pronounced glycosylation defect [16]. HSP90 inhibitors result in a relative increase of FLT3 in localization of cell membrane [38,97].…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

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Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

Chen

2019

Hematology

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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.

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Section: Prognosis and Current Treatments Of Mutant Flt3 In Patientsmentioning

confidence: 99%

Section: Prognosis and Current Treatments Of Mutant Flt3 In Patientsmentioning

confidence: 99%

“…Zhang et al [38] believe that oncoproteins cause UPR, while UPR causes HSP90 activation to stabilize oncoproteins and form positive feedback to cause cancer progression (Figure 2).…”

Section: Abnormal Signal Of Mutant Flt3 With Different Glycosylation mentioning

confidence: 99%

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

Chen

2019

Hematology

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GRP94 promotes anoikis resistance and peritoneal metastasis through YAP/TEAD1 pathway in gastric cancer

Shi,

Lu,

et al. 2024

iScience

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NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia

Chen,

Zou,

Găman

et al. 2023

Cell Death Discov.

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The internal tandem duplication of the juxtamembrane domain of the FMS-like tyrosine kinase 3 (FLT3-ITD) is the most common genetic change in acute myeloid leukemia (AML), and about 30% of all AMLs harbor a FLT3-ITD mutation. Even though FLT3 inhibitors have displayed encouraging effects in FLT3-ITD-mutated AML, the extent of the clinical response to these compounds is cut short due to the rapid development of drug resistance. Evidence has shown that FLT3-ITD triggered activation of oxidative stress signaling may exert a pivotal role in drug resistance. The downstream pathways of FLT3-ITD, including STAT5, PI3K/AKT, and RAS/MAPK, are considered to be major oxidative stress signaling pathways. These downstream pathways can inhibit apoptosis and promote proliferation and survival by regulating apoptosis-related genes and promoting the generation of reactive oxygen species (ROS) through NADPH oxidase (NOX) or other mechanisms. Appropriate levels of ROS may promote proliferation, but high levels of ROS can lead to oxidative damage to the DNA and increase genomic instability. In addition, post-translational modifications of FLT3-ITD and changes in its subcellular localization can affect downstream signaling which may also be one of the mechanisms leading to drug resistance. In this review, we summarized the research progress on NOX mediated oxidative stress signaling and its relationship with drug resistance in FLT3-ITD AML, and discuss the possible new targets in FLT3-ITD signal blocking to reverse drug resistance in FLT3-ITD-mutated AML.

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GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells

Abstract: Our paper reported that FLT3-ITD-positive AML cells are addicted to HSP90 activity, and that the HSP90 family member GRP94 is required for aberrant endoplasmic reticulum retention of FLT3-ITD. We have reason to question the provenance of the data shown in Figures 2E,

Cited by 7 publications

References 0 publications

Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

GRP94 promotes anoikis resistance and peritoneal metastasis through YAP/TEAD1 pathway in gastric cancer

NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia

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