Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

Area of Science:

• Oncology
• Cell Biology
• Molecular Medicine

Background:

• Notch signaling is implicated in various cancers and chemotherapy response.
• Its role in acute myeloid leukemia (AML) and leukemia-stromal cell crosstalk is debated.
• Previous work demonstrated Notch inhibition's effect on lymphoid neoplasms.

Purpose of the Study:

• To investigate the Notch pathway's role in AML cell proliferation, survival, and chemoresistance.
• To analyze the impact of bone marrow mesenchymal stromal cells (MSCs) from healthy donors and AML patients on AML cells.
• To evaluate Notch inhibition as a therapeutic strategy for AML.

Main Methods:

• Co-culture of AML cells with MSCs from healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*).
• Assessment of Notch pathway components (Notch1, Jagged1, HES1) and signaling activation in AML cells.
• Pharmacological inhibition of Notch using blocking antibodies and gamma-secretase inhibitors (GSIs) combined with chemotherapy.

Main Results:

• hBM-MSCs* exhibited higher Notch signaling components than hBM-MSCs.
• hBM-MSCs* enhanced AML cell proliferation and chemoresistance more effectively than hBM-MSCs via Notch activation.
• Notch inhibition reduced stromal support, induced apoptosis, and decreased STAT3, AKT, and NF-κB levels in AML cells.

Conclusions:

• Notch signaling is crucial for AML cell proliferation and chemoresistance, particularly in the context of bone marrow stromal cell interactions.
• Notch inhibition effectively overcomes stromal-mediated chemoresistance in AML.
• Targeting Notch signaling presents a promising therapeutic avenue for AML, potentially extending beyond lymphoid neoplasms.