TY - JOUR
T1 - Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo
AU - Rummelt, Christoph
AU - Gorantla, Sivahari P.
AU - Meggendorfer, Manja
AU - Charlet, Anne
AU - Endres, Cornelia
AU - Döhner, Konstanze
AU - Heidel, Florian H.
AU - Fischer, Thomas
AU - Haferlach, Torsten
AU - Duyster, Justus
AU - von Bubnoff, Nikolas
N1 - Funding Information:
Acknowledgements This work was supported by a grant to NvB from the Deutsche Forschungsgemeinschaft No. BU 2508/4–1, by a grant to JD and NvB from the Bundesministerium für Bildung und Forschung (NGFNplus) and by a grant to JD and NvB from the José Carreras Stiftung No. 106682. Proofreading was performed by Dr. Marie Follo Author contributions NvB, JD, and CR designed experiments and wrote the manuscript. CR, SPG, AC, and CE performed experiments. MM, KD, FH, TF, and TH provided patient samples and patient data. TF provided constructs.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85094946262&partnerID=8YFLogxK
U2 - 10.1038/s41375-020-01077-1
DO - 10.1038/s41375-020-01077-1
M3 - Journal articles
AN - SCOPUS:85094946262
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -
