4.7 Article

Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo

Journal

LEUKEMIA
Volume 35, Issue 7, Pages 2017-2029

Publisher

SPRINGERNATURE
DOI: 10.1038/s41375-020-01077-1

Keywords

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Funding

  1. Deutsche Forschungsgemeinschaft [BU 2508/4-1]
  2. Bundesministerium fur Bildung und Forschung (NGFNplus)
  3. Jose Carreras Stiftung [106682]

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One important limitation of FLT3 tyrosine kinase inhibitors in FLT3-ITD positive AML is the development of resistance. Research has found that JAK1 V658F mutation leads to reactivation of the CSF2RB-STAT5 pathway, while JAK family activating mutations induce resistance to FLT3-ITD inhibition, which can be overcome by dual FLT3/JAK inhibition.
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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