ArticleCancers2019
FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM.
Article in Cancers, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 48 citations in OpenAlex.
- Cross-Talk Between Histamine HPharmacology research & perspectives · 2026Article
- Overexpressed RPS6KA1 and its potential diagnostic value in head and neck squamous cell carcinoma.Discover oncology · 2025Article
- RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia.Nature communications · 2025Article
- RSK1 dependency in FLT3-ITD acute myeloid leukemia.Blood cancer journal · 2024Article
- Punicalagin as a novel selective aryl hydrocarbon receptor (AhR) modulator upregulates AhR expression through the PDK1/p90RSK/AP-1 pathway to promote the anti-inflammatory response and bactericidal activity of macrophages.Cell communication and signaling : CCS · 2024Article
- Targeting USP14/UCHL5: A Breakthrough Approach to Overcoming Treatment-Resistant FLT3-ITD-Positive AML.International journal of molecular sciences · 2024Article
- Blockage of BCL-XL overcomes venetoclax resistance across BCL2+ lymphoid malignancies irrespective of BIM status.Blood advances · 2024Article
- Homoharringtonine: updated insights into its efficacy in hematological malignancies, diverse cancers and other biomedical applications.European journal of medical research · 2024Review
- Paclitaxel mediates the PI3K/AKT/mTOR pathway to reduce proliferation of FLT3‑ITDExperimental and therapeutic medicine · 2024Article
- Kinase signalling adaptation supports dysfunctional mitochondria in disease.Frontiers in molecular biosciences · 2024Review
- Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies.International journal of molecular sciences · 2023Review
- Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection.iScience · 2023Article
- The ribosomal protein S6 kinase alpha-1 (RPS6KA1) induces resistance to venetoclax/azacitidine in acute myeloid leukemia.Leukemia · 2023Article
- Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma.Molecular oncology · 2023Article
- Identification and validation of a novel CD8+ T cell-associated prognostic model based on ferroptosis in acute myeloid leukemia.Frontiers in immunology · 2023Article
- Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia.International journal of molecular sciences · 2022Article
- Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- Molecular dissection of a hyper-aggressive CBFB-MYH11/FLT3-ITD-positive acute myeloid leukemia.Journal of translational medicine · 2022Article
- Pentacyclic triterpenoid ursolic acid induces apoptosis with mitochondrial dysfunction in adult T-cell leukemia MT-4 cells to promote surrounding cell growth.Medical oncology (Northwood, London, England) · 2022Article
- Progress in understanding the mechanisms of resistance to BCL-2 inhibitors.Experimental hematology & oncology · 2022Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously found that FLT3-ITD activates the mTORC1/S6K/4EBP1 pathway cooperatively through the STAT5/PIM and PI3K/AKT pathways to promote proliferation and survival by enhancing the eIF4F complex formation required for cap-dependent translation. Here, we show that, in contrast to BCR/ABL causing Ph-positive leukemias, FLT3-ITD distinctively activates the serine/threonine kinases RSK1/2 through activation of the MEK/ERK pathway and PDK1 to transduce signals required for FLT3-ITD-dependent, but not BCR/ABL-dependent, proliferation and survival of various cells, including MV4-11. Activation of the MEK/ERK pathway by FLT3-ITD and its negative feedback regulation by RSK were mediated by Gab2/SHP2 interaction. RSK1 phosphorylated S6RP on S235/S236, TSC2 on S1798, and eIF4B on S422 and, in cooperation with PIM, on S406, thus activating the mTORC1/S6K/4EBP1 pathway and eIF4B cooperatively with PIM. RSK1 also phosphorylated Bad on S75 and downregulated BIM-EL in cooperation with ERK. Furthermore, inhibition of RSK1 increased sensitivities to BH3 mimetics inhibiting Mcl-1 or Bcl-2 and induced activation of Bax, leading to apoptosis, as well as inhibition of proliferation synergistically with inhibition of PIM or PI3K. Thus, RSK1 represents a promising target, particularly in combination with PIM or PI3K, as well as anti-apoptotic Bcl-2 family members, for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML.
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Registered trials
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