title: Chemical genomic screening identifies LY294002 as a modulator of glucocorticoid resistance in MLL-rearranged infant ALL.
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.
authors: Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: J A P
authors: JA
authors: Spijkers-Hagelstein
authors: Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: S S
authors: SS
authors: Pinhanços
authors: Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: P
authors: P
authors: Schneider
authors: Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: R
authors: R
authors: Pieters
authors: Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: R W
authors: RW
authors: Stam
mesh_terms: D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D004351:Drug Resistance; D015321:Gene Rearrangement; D023281:Genomics; D005938:Glucocorticoids / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D011239:Prednisolone / Q000494:pharmacology*; D034622:RNA Interference; D017452:Receptors, IgG / Q000502:physiology
chemical_list: D002867:Chromones; C489017:FCGR1A protein, human; D005938:Glucocorticoids; C497422:KMT2A protein, human; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017452:Receptors, IgG; D051788:Myeloid-Lymphoid Leukemia Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011239:Prednisolone; D011495:Histone-Lysine N-Methyltransferase
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