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Acute Leukemias

Chemical genomic screening identifies LY294002 as a modulator of glucocorticoid resistance in MLL-rearranged infant ALL

Leukemia volume 28, pages 761–769 (2014)Cite this article

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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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Acknowledgements

The authors gratefully thank all the members and participating hospitals of the INTERFANT-99 study groups for supporting our research by generously providing leukemic samples. This study was funded by KIKA (stichting KinderenKankervrij) (JAPS-H). RWS was financially supported by the Dutch Cancer Society (KWF Kankerbestrijding). The institutions funding this research did not participate in study design, data collection, data analysis, data interpretation or writing of the report. All authors had full access to all the data at all time and shared final responsibility for the decision to submit for publication.

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  1. Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children’s Hospital, Rotterdam, The Netherlands

    J A P Spijkers-Hagelstein, S S Pinhanços, P Schneider, R Pieters & R W Stam

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  1. J A P Spijkers-Hagelstein
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  2. S S Pinhanços
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  3. P Schneider
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  4. R Pieters
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Correspondence to R W Stam.

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JAPS-H designed and performed research and wrote the paper; SSP and PS performed research; RP and RWS designed and supervised research, wrote and reviewed the paper.

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Spijkers-Hagelstein, J., Pinhanços, S., Schneider, P. et al. Chemical genomic screening identifies LY294002 as a modulator of glucocorticoid resistance in MLL-rearranged infant ALL. Leukemia 28, 761–769 (2014). https://doi.org/10.1038/leu.2013.245

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