Abstract
The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.
Highlights
Acute lymphoblastic leukemia (ALL) is one of the most common childhood cancers and can originate both from the B-lineage (BALL) and the T-lineage (T-ALL)
In order to understand how long-term dexamethasone treatment affects B cell ALL (B-ALL) cells, we used three dexamethasone-sensitive cell lines: 697 (half-maximal effective concentration (EC50) = 8.2 nM), NALM-6 (EC50 = 3.9 nM), and RS4;11 (EC50 = 1.5 nM), and the dexamethasone-insensitive cell line TANOUE (EC50 >10 μM). These cell lines were cultured with an increasing concentration of dexamethasone for 90 days. Another set of cell lines was cultured with an equivalent amount of dimethyl sulfoxide (DMSO)
We observed that all three dexamethasonesensitive cell lines cultured in the presence of dexamethasone became highly resistant to dexamethasone, while DMSO-treated
Summary
Acute lymphoblastic leukemia (ALL) is one of the most common childhood cancers and can originate both from the B-lineage (BALL) and the T-lineage (T-ALL) Glucocorticoids, such as dexamethasone and prednisolone, are important drugs for the treatment of ALL.[1] In combination with chemotherapeutic agents, glucocorticoids help to achieve clinical remission, and sensitivity to glucocorticoids is considered as a positive prognostic indicator. GR inhibits activator protein-1 (AP-1)- and nuclear factor-κB (NF-κB)-regulated gene transcription, and at the same time promotes glucocorticoidresponsive element-driven gene transcription.[2] Besides, inhibition of AP-1- and NF-κB-regulated gene transcription, cooperation between AP-1 and GR in transcription,[3] and crosstalk between NFκB and GR4,5 have been reported, which suggests a contextdependent regulation of AP-1 and NF-κB rather than only inhibitory effects
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