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Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo
- Source :
- Leukemia; July 2021, Vol. 35 Issue: 7 p2017-2029, 13p
- Publication Year :
- 2021
-
Abstract
- An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB–STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n= 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n= 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.
Details
- Language :
- English
- ISSN :
- 08876924 and 14765551
- Volume :
- 35
- Issue :
- 7
- Database :
- Supplemental Index
- Journal :
- Leukemia
- Publication Type :
- Periodical
- Accession number :
- ejs54562613
- Full Text :
- https://doi.org/10.1038/s41375-020-01077-1