HemaBites showcase hematology news and short commentaries on recent high-impact articles published in international journals. This blog will keep you up to date with the latest developments and discoveries in the field of hematology.

Friday, April 6, 2018

Acute Myeloid Leukemia (AML) – Hitting the FLT3 Target

Acute Myeloid Leukemia (AML) – Hitting the FLT3 Target

Lars Bullinger 

Department of Hematology, Oncology and Tumor Immunology; and Charité-University-Medicine Berlin, Germany

In acute myeloid leukemia (AML), FLT3 tyrosine kinase mutations such as internal tandem duplications (ITD) are often associated with an unfavorable prognosis, and thus many FLT3-ITD patients undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). While outcome of relapse after allo-HSCT is usually dismal, treatment with sorafenib, a multi-targeted tyrosine kinase inhibitor (TKI), has resulted in durable remission in some patients (Metzelder et al. 2017). Mathew and colleagues now provide a stunning molecular rationale for this observation (Mathew et al. 2018). They could demonstrate that kinase inhibitors like sorafenib can increase the production of IL-15 by FLT3-ITD positive AML cells. IL-15 then synergizes with the allogeneic CD8+ T-cell response, thereby leading to long-term survival in FLT3-ITD mouse leukemia models. Mechanistically, sorafenib leads to a reduction in the expression of the transcription factor ATF4, thereby inhibiting the interferon regulatory factor 7 (IRF7) activation block, which in turn enhances IL-15 transcription. Thus, in patients with FLT3-ITD positive AML relapsing after allo-HSCT, multi-targeted TKI treatment might confer an immune-mediated cure. Given the recent approval of the multi-targeted TKI midostaurin for FLT3 mutant AML (Stone et al. 2017), it will be interesting to see whether TKI use not only in case of relapse, but also as maintenance therapy following allo-HSCT will have a positive impact on outcome.


Figure 1: Mathew and colleagues propose that FLT3 inhibition by sorafenib (or other TKIs) leads to increased IL-15 transcription because it takes away downstream FLT3 receptor tyrosine kinase signaling, which normally leads to ATF4 production. Diminished ATF4 levels result in decreased inhibition of IRF7 phosphorylation and activation. This in turn leads to more active phosphorylated IRF7, which can translocate to the nucleus, where it activates IL-15 transcription. The link between oncogenic FLT3 signaling and ATF4-mediated inhibition of IL-15 production could serve as tumor escape mechanism.[Scheme kindly provided by R. Zeiser]


1. Mathew et al. Nat Med. 2018 Mar;24(3):282-291. doi: 10.1038/nm.4484.

2. Metzelder et al. Eur J Cancer. 2017 Nov;86:233-239. doi: 10.1016/j.ejca.2017.09.016.

3. Stone et al. N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359.​