What question did this study set out to answer?

To identify the mechanism driving FLT3 inhibitor-induced upregulation of niche-homing molecules and test whether dual CXCR4/E-selectin inhibition overcomes bone marrow-mediated drug resistance in FLT3-mutant AML.

April 21, 2023LeukemiaOpen Access

FLT3 inhibitors upregulate CXCR4 and E-selectin ligands via ERK suppression in AML cells and CXCR4/E-selectin inhibition enhances anti-leukemia efficacy of FLT3-targeted therapy in AML

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Authors

YJYannan JiaThe University of Texas MD Anderson Cancer Center WZWeiguo ZhangThe University of Texas MD Anderson Cancer Center MBMahesh BasyalThe University of Texas MD Anderson Cancer Center

Discussion

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Implication

Preclinical study reveals dual CXCR4 and E-selectin inhibition enhances FLT3-targeted therapy in AML models, suggesting a strategy to overcome bone marrow microenvironment-mediated resistance.

Key Points

To identify the mechanism driving FLT3 inhibitor-induced upregulation of niche-homing molecules and test whether dual CXCR4/E-selectin inhibition overcomes bone marrow-mediated drug resistance in FLT3-mutant AML.
Quantified CXCR4 and E-selectin ligand expression in patient AML blasts and cell lines exposed to FLT3 inhibitors or MEK pathway inhibitors (selumetinib, pimasertib).
Evaluated leukemia cell adhesion, transwell migration, and intravital two-photon bone marrow motility after treatment with the dual CXCR4/E-selectin antagonist GMI-1359.
Treated patient-derived xenograft (PDX) mouse models of FLT3-mutant AML with GMI-1359 combined with quizartinib or sorafenib to assess survival, tumor burden, and normal hematopoiesis.
FLT3 inhibition transcriptionally upregulated CXCR4 and E-selectin ligands in AML cells through suppression of ERK/MAPK signaling rather than AKT/mTOR or STAT5 pathways.
GMI-1359 infusion accelerated AML cell motility in murine bone marrow by over 100% within 3.5 hours (reaching 5.4 µm/min), releasing blasts into the peripheral circulation.
Combined GMI-1359 and quizartinib extended median survival in PDX mice to 158 days compared to 82.5 days for vehicle, 79 days for quizartinib alone, and 128 days for GMI-1359 alone (p < 0.0001).

Cite This Study

Jia et al. (2023) studied this question.

synapsesocial.com/papers/6a79bcaa0b10e55359892514 https://doi.org/10.1038/s41375-023-01897-x

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April 21, 2023LeukemiaOpen Access

FLT3 inhibitors upregulate CXCR4 and E-selectin ligands via ERK suppression in AML cells and CXCR4/E-selectin inhibition enhances anti-leukemia efficacy of FLT3-targeted therapy in AML

View Full Paper

Ask AI

Bookmark

Authors

YJYannan JiaThe University of Texas MD Anderson Cancer Center WZWeiguo ZhangThe University of Texas MD Anderson Cancer Center MBMahesh BasyalThe University of Texas MD Anderson Cancer Center

Discussion

Member takes

Implication

Preclinical study reveals dual CXCR4 and E-selectin inhibition enhances FLT3-targeted therapy in AML models, suggesting a strategy to overcome bone marrow microenvironment-mediated resistance.

Key Points

To identify the mechanism driving FLT3 inhibitor-induced upregulation of niche-homing molecules and test whether dual CXCR4/E-selectin inhibition overcomes bone marrow-mediated drug resistance in FLT3-mutant AML.
Quantified CXCR4 and E-selectin ligand expression in patient AML blasts and cell lines exposed to FLT3 inhibitors or MEK pathway inhibitors (selumetinib, pimasertib).
Evaluated leukemia cell adhesion, transwell migration, and intravital two-photon bone marrow motility after treatment with the dual CXCR4/E-selectin antagonist GMI-1359.
Treated patient-derived xenograft (PDX) mouse models of FLT3-mutant AML with GMI-1359 combined with quizartinib or sorafenib to assess survival, tumor burden, and normal hematopoiesis.
FLT3 inhibition transcriptionally upregulated CXCR4 and E-selectin ligands in AML cells through suppression of ERK/MAPK signaling rather than AKT/mTOR or STAT5 pathways.
GMI-1359 infusion accelerated AML cell motility in murine bone marrow by over 100% within 3.5 hours (reaching 5.4 µm/min), releasing blasts into the peripheral circulation.
Combined GMI-1359 and quizartinib extended median survival in PDX mice to 158 days compared to 82.5 days for vehicle, 79 days for quizartinib alone, and 128 days for GMI-1359 alone (p < 0.0001).

Cite This Study

Jia et al. (2023) studied this question.

synapsesocial.com/papers/6a79bcaa0b10e55359892514 https://doi.org/10.1038/s41375-023-01897-x

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