AML alters bone marrow stromal cell osteogenic commitment via Notch signaling

Area of Science:

• Hematology
• Oncology
• Cell Biology

Background:

• Acute myeloid leukemia (AML) is a heterogeneous cancer characterized by immature myeloid blast accumulation in the bone marrow (BM).
• AML disrupts normal hematopoiesis and alters the BM microenvironment, creating a niche that supports leukemogenesis.
• Bone marrow stromal cells (BMSCs) are crucial for BM niche formation, influencing adipocyte and osteogenic cell differentiation.

Purpose of the Study:

• To investigate the mechanisms by which AML cells affect the osteogenic differentiation of normal BMSCs.
• To determine the role of direct cell-cell interaction and specific signaling pathways in AML-induced alterations of the BM niche.

Main Methods:

• Utilized a 2D co-culture system to study the effect of AML cell lines and primary blasts on normal BMSCs.
• Investigated osteogenic commitment using early and late osteogenic markers.
• Performed mechanistic studies to identify signaling pathways involved, including Notch signaling, and used a γ-secretase inhibitor to block Notch activation.

Main Results:

• AML cells, but not normal hematopoietic cells, induced ineffective osteogenic commitment in BMSCs, marked by increased tissue non-specific alkaline phosphatase (TNAP) without late-stage gene upregulation.
• Direct interaction between AML cells and BMSCs was essential for altering osteogenic differentiation.
• AML-mediated Notch activation in BMSCs was identified as a key mechanism contributing to ineffective osteogenic commitment, and its inhibition abrogated TNAP upregulation.

Conclusions:

• AML infiltration promotes a leukemia-supportive pre-osteoblast-rich niche in the BM.
• This niche formation is partly attributed to AML-induced activation of Notch signaling in BMSCs.
• Targeting Notch signaling may offer a therapeutic strategy to disrupt the AML-supportive BM microenvironment.