The stromal microenvironment provides an escape route from FLT3 inhibitors through the GAS6-AXL-STAT5 axis

Orlova, Anna; Neubauer, Heidi A.; Moriggl, Richard

doi:10.3324/haematol.2019.225862

Cited by 13 publications

(9 citation statements)

References 19 publications

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“…Variables in tissue concentration of gilteritinib potentially plays an important role in the biphasic responses through its impactive AXL off-target inhibition. AXL, a member of phosphatidylserine-sensing receptor tyrosine kinases, the TAM family (Tyro3, AXL, and Mer), is significantly up-regulated in AML patient samples ( 34 ). Mice lacking all three receptors had impaired hemostasis and thrombocytopenia potentially due to platelet dysfunction and defective megakaryopoiesis ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

et al. 2020

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Numerous recurrent genetic mutations are known to occur in acute myeloid leukemia (AML). Among these common mutations, Fms-like tyrosine kinase 3 remains as one of the most frequently mutated genes in AML. We observed apparent marrow expansion of megakaryocytes in three out of six patients with Flt3-mutated AML following treatment with a recently FDA-approved Flt3 inhibitor, gilteritinib which possesses activity against internal tandem duplication and tyrosine kinase domain Flt3 mutations and also inhibits tyrosine kinase AXL. To assess whether biopsy findings can be attributed to promotion of megakaryocytic (Mk) differentiation with gilteritinib, we devised a cellular assay by overexpressing double mutated Flt3-ITDY591F/Y919F in chronic myeloid leukemia cell line K562 to study Mk differentiation in the presence of Flt3 and AXL inhibitors with non-mutually exclusive mechanisms. These experiments demonstrated the lack of direct effect Flt3 inhibitors gilteritinib and quizartinib on megakaryocytic differentiation at either transcriptional or phenotypic levels, and highlighted antileukemic effects of AXL receptor tyrosine kinase inhibitor and its potential role in megakaryocytic development.

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Section: Discussionmentioning

confidence: 99%

Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

et al. 2020

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“…communication with commensals or the AXL/MER/TERO tyrosine kinase receptor family and their ligands [ 33 ]. AXL tyrosine kinase is a direct target of STAT5 in hematopoietic cell types, facilitating immune cell control or prolonged pYSTAT5 action when activated by its ligands [ 62 ]. Therefore, the signaling network must be tightly regulated to maintain intestinal homeostasis.…”

Section: Intestinal Epithelial Cells (Iec) Intestinal Stem Cells (Isc) and Niche Cellsmentioning

confidence: 99%

A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation

et al. 2021

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Cytokines, growth factors or hormones take action through the JAK/STAT5 signaling pathway, which plays a critical role in regulating the intestinal response to infection and inflammation. However, the way in which STAT5 regulates intestinal epithelial compartment is largely ignored due to the lack of genetic tools for proper exploration and because the two STAT5 transcription factors (STAT5A and STAT5B) have some redundant but also distinct functions. In this review article, by focusing on STAT5 functions in the intestinal undifferentiated and differentiated epithelia, we discuss major advances of the growth factor/cytokine-JAK/STAT5 research in view of intestinal mucosal inflammation and immunity. We highlight the gap in the research of the intestinal STAT5 signaling to anticipate the gastrointestinal explorative insights. Furthermore, we address the critical questions to illuminate how STAT5 signaling influences intestinal epithelial cell differentiation and stem cell regeneration during homeostasis and injury. Overall, our article provides a centric view of the relevance of the relationship between chronic inflammatory diseases and JAK/STAT5 pathway and it also gives an example of how chronic infection and inflammation pirate STAT5 signaling to worsen intestinal injuries. Importantly, our review suggests how to protect a wound healing from gastrointestinal diseases by modulating intestinal STAT5.

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“…In 2018, the FDA approved gilteritinib for the treatment of R/R FLT3-mutated AML after the promising results of the ADMIRAL trial, a randomized, open label, multicenter phase III study comparing gilteritinib or conventional chemotherapy for R/R FLT3-mutated AML patients [29]. This new agent has a potent activity against both ITD and TKD mutations, blocking FLT3 and also AXL activity, whose increased expression has been attributed to a mechanism of chemo-refractoriness [30]. As other FLT3 inhibitors, gilteritinib has been tested alone or in combination with HMA with promising results.…”

Section: Fms-related Tyrosine Kinase 3 (Flt3) Inhibitorsmentioning

confidence: 99%

From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia

Gurnari

Voso

Maciejewski

et al. 2020

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders characterized by abnormal proliferation of undifferentiated myeloid progenitors, impaired hematopoiesis, and variable response to therapy. To date, only about 30% of adult patients with AML become long-term survivors and relapse and/or disease refractoriness are the major cause of treatment failure. Thus, this is an urgent unmet clinical need and new drugs are envisaged in order to ameliorate disease survival outcomes. Here, we review the latest therapeutic approaches (investigational and approved agents) for AML treatment. A specific focus will be given to molecularly targeted therapies for AML as a representation of possible agents for precision medicine. We will discuss experimental and preclinical data for FLT3, IDH1, BCL-2, Hedgehog pathway inhibitors, and epitherapy.

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The stromal microenvironment provides an escape route from FLT3 inhibitors through the GAS6-AXL-STAT5 axis

Cited by 13 publications

References 19 publications

Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation

From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia

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