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Can I read Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo on EtoBox?
Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo by Rummelt, Christoph; Gorantla, Sivahari P.; Meggendorfer, Manja; Charlet, Anne; Endres, Cornelia; Döhner, Konstanze; Heidel, Florian H.; Fischer, Thomas; Haferlach, Torsten; Duyster, Justus; von Bubnoff, Nikolas is a Medicine article available to read on EtoBox.
What is Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo about?
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.
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- Author
- Rummelt, Christoph; Gorantla, Sivahari P.; Meggendorfer, Manja; Charlet, Anne; Endres, Cornelia; Döhner, Konstanze; Heidel, Florian H.; Fischer, Thomas; Haferlach, Torsten; Duyster, Justus; von Bubnoff, Nikolas
- Publisher
- Nature Publishing Group; Springer Science and Business Media LLC (ISSN 0887-6924)
- Published
- 2020
- Language
- EN
- Field
- Medicine (Health Sciences)