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.2018.189399

Cited by 6 publications

(5 citation statements)

References 13 publications

(20 reference statements)

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“…Additionally, a fusion protein's capability to hijack an alternative chaperone has previously been reported. Fusion of FMS-like tyrosine kinase-3 (FLT3) with the HLH-transcription factor TEL (TEL/FLT3) forms dimers and is mediated by chaperone GRP94 [64]. However, fusion with ETS variant transcription factor 6 (ETV6) produces an ETV6/FLT3 oncoprotein fusion that is constitutively active and utilizes Hsp90, a chaperone known to stabilize a number of proteins required for tumor progression [65].…”

Section: Categorical Dissection Of the Different Domains Thatmentioning

confidence: 99%

Native and tagged CENP-A histones are functionally inequivalent

Bui,

Baek,

Bentahar

et al. 2024

Epigenetics & Chromatin

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Background Over the past several decades, the use of biochemical and fluorescent tags has elucidated mechanistic and cytological processes that would otherwise be impossible. The challenging nature of certain nuclear proteins includes low abundancy, poor antibody recognition, and transient dynamics. One approach to get around those issues is the addition of a peptide or larger protein tag to the target protein to improve enrichment, purification, and visualization. However, many of these studies were done under the assumption that tagged proteins can fully recapitulate native protein function. Results We report that when C-terminally TAP-tagged CENP-A histone variant is introduced, it undergoes altered kinetochore protein binding, differs in post-translational modifications (PTMs), utilizes histone chaperones that differ from that of native CENP-A, and can partially displace native CENP-A in human cells. Additionally, these tagged CENP-A-containing nucleosomes have reduced centromeric incorporation at early G1 phase and poorly associates with linker histone H1.5 compared to native CENP-A nucleosomes. Conclusions These data suggest expressing tagged versions of histone variant CENP-A may result in unexpected utilization of non-native pathways, thereby altering the biological function of the histone variant.

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Section: Categorical Dissection Of the Different Domains Thatmentioning

confidence: 99%

Native and tagged CENP-A histones are functionally inequivalent

Bui,

Baek,

Bentahar

et al. 2024

Epigenetics & Chromatin

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“…ER localization is at least partly mediated by the chaperone protein GRP94. Pharmacologi-cal inhibition or siRNA-mediated depletion of GRP94 resulted in enhanced membrane translocation of FLT3-ITD (358). The mechanism by which STAT5 is phosphorylated by FLT3 has been thoroughly studied.…”

Section: H Signaling From Oncogenic Flt3mentioning

confidence: 99%

“…In other words, inhibition or downregulation of HSP90 can be a means of downregulating FLT3-ITD (243). GRP94 is another HSP90 family protein that mediates ER retention of FLT3-ITD, where it activates STAT5 signaling (358). Inhibition of GRP94 results in enhanced plasma membrane localization of FLT3 and inhibition of STAT5 signaling.…”

Section: B Targeting Chaperone Proteinsmentioning

confidence: 99%

“…FLT3-ITD induces expression of p21, and therefore, inhibition of FLT3-ITD results in transcriptional repression of p21 (1). Pharmacological inhibition of FLT3 stabilizes and enhances membrane localization of FLT3-ITD (337,358). This type of feedback-loop can, in turn, lead to the development of resistance to the drug where drug treatment increases the number of oncogenic receptors.…”

Section: E Flt3 Inhibition and Feedback Regulationmentioning

confidence: 99%

“…The MDM2 inhibitor NVP-HDM201 shows synergy with midostaurin in FLT3-ITD-positive AML (283). Since inhibition of FLT3-ITD kinase activity by tyrosine kinases inhibitors enhances membrane translocation, the use of tyrosine kinase inhibitor enhances the efficacy of FLT3-directed immunotherapy for AML (262,358). Use of FLT3 inhibitor in combination with the DNA methyltransferase decitabine (5-aza-2-deoxycytidine, DEC) and 5-azacitidine (AZA) has been tested and was shown to be beneficial for older AML patients (36).…”

Section: G Targeting Flt3 In Combination With Other Proteinsmentioning

confidence: 99%

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FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi

Rönnstrand

2019

Physiological Reviews

133

147

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FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

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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

Cited by 6 publications

References 13 publications

Native and tagged CENP-A histones are functionally inequivalent

Native and tagged CENP-A histones are functionally inequivalent

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

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

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