Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation
(2019) In npj Genomic Medicine 4(1).- 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... (More)
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.
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- author
- Chougule, Rohit A. LU ; Shah, Kinjal LU ; Moharram, Sausan A. LU ; Vallon-Christersson, Johan LU and Kazi, Julhash U. LU
- organization
- publishing date
- 2019-04-04
- type
- Contribution to journal
- publication status
- published
- subject
- in
- npj Genomic Medicine
- volume
- 4
- issue
- 1
- article number
- 7
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85063984068
- pmid:30962949
- ISSN
- 2056-7944
- DOI
- 10.1038/s41525-019-0082-y
- language
- English
- LU publication?
- yes
- id
- 3661c149-bc79-4dee-8088-bbae401eedce
- date added to LUP
- 2019-04-24 08:39:44
- date last changed
- 2024-09-18 17:16:06
@article{3661c149-bc79-4dee-8088-bbae401eedce, abstract = {{<p>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.</p>}}, author = {{Chougule, Rohit A. and Shah, Kinjal and Moharram, Sausan A. and Vallon-Christersson, Johan and Kazi, Julhash U.}}, issn = {{2056-7944}}, language = {{eng}}, month = {{04}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{npj Genomic Medicine}}, title = {{Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation}}, url = {{http://dx.doi.org/10.1038/s41525-019-0082-y}}, doi = {{10.1038/s41525-019-0082-y}}, volume = {{4}}, year = {{2019}}, }