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Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

Chougule, Rohit A. LU ; Shah, Kinjal LU ; Moharram, Sausan A. LU ; Vallon-Christersson, Johan LU orcid and Kazi, Julhash U. LU orcid (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
; ; ; and
organization
publishing date
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
  • pmid:30962949
  • scopus:85063984068
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
2024-03-03 01:04:09
@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}},
}