ArticleLeukemia2014
Chemical genomic screening identifies LY294002 as a modulator of glucocorticoid resistance in MLL-rearranged infant ALL.
Article in Leukemia, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.Experimental hematology & oncology · 2023Article
- Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes.Frontiers in oncology · 2023Article
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- CPDR: An R Package of Recommending Personalized Drugs for Cancer Patients by Reversing the Individual's Disease-Related Signature.Frontiers in pharmacology · 2022Article
- A comprehensive genome-wide analysis of long non-coding RNA and mRNA expression profiles of JAK2V617F-positive classical myeloproliferative neoplasms.Bioengineered · 2021Article
- Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines.Cancer cell international · 2020Article
- Differential network analysis and protein-protein interaction study reveals active protein modules in glucocorticoid resistance for infant acute lymphoblastic leukemia.Molecular medicine (Cambridge, Mass.) · 2019Article
- Molecular mechanisms contributing to glucocorticoid resistance in lymphoid malignancies.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- A review of connectivity map and computational approaches in pharmacogenomics.Briefings in bioinformatics · 2018Review
- The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.Leukemia · 2017Article
- MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations.Oncotarget · 2017Article
- Network-based expression analysis reveals key genes related to glucocorticoid resistance in infant acute lymphoblastic leukemia.Cellular oncology (Dordrecht, Netherlands) · 2017Article
- 2-Deoxy-D-glucose Restore Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia via Modification of N-Linked Glycosylation in an Oxygen Tension-Independent Manner.Oxidative medicine and cellular longevity · 2017Article
- Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol.Leukemia · 2016Article
- Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen.Oncotarget · 2016Article
- Using Pharmacogenomic Databases for Discovering Patient-Target Genes and Small Molecule Candidates to Cancer Therapy.Frontiers in pharmacology · 2016Review
- PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia.Oncotarget · 2015Article
- Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: a Connectivity Mapping analysis and an experimental study.American journal of cancer research · 2015Article
- The evolution of clinical trials for infant acute lymphoblastic leukemia.Blood cancer journal · 2014Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Successful treatment results for MLL-rearranged Acute Lymphoblastic Leukemia (ALL) in infants remain difficult to achieve. Significantly contributing to therapy failure is poor response to glucocorticoids (GCs), like prednisone. Thus, overcoming resistance to these drugs may be a crucial step towards improving prognosis. We defined a gene signature that accurately discriminates between prednisolone-resistant and prednisolone-sensitive MLL-rearranged infant ALL patient samples. In the current study, we applied Connectivity Map analysis to perform an in silico screening for agents capable of reversing the prednisolone-resistance profile and induce sensitivity. These analyses revealed that LY294002, a PI3K inhibitor, would potentially fulfill this task. Subsequent validation experiments demonstrated that indeed LY294002, and other known PI3K inhibitors, markedly sensitized otherwise resistant MLL-rearranged ALL cells to prednisolone in vitro. Using quantitative RT-PCR analyses, we validated the modulating effects of the PI3K inhibitors on the expression of the genes present in our prednisolone-resistance profile. Interestingly, prednisolone-sensitizing actions may be mediated by inhibition of FCGR1B. Moreover, only high-level expression of FCGR1B showed to be predictive for a poor prognosis and shRNA-mediated knock-down of FCGR1B led to in vitro prednisolone sensitization. Thus, implementing FDA-approved PI3K inhibitors in current treatments may potentially improve the GC response and prognosis in patients with MLL-rearranged ALL.
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