Brain-Decellularized ECM-Based 3D Myeloid Sarcoma Platform: Mimicking Adaptive Phenotypic Alterations in the Brain

Area of Science:

• * Hematology
• * Oncology
• * Neuroscience

Background:

• * Leukemia can infiltrate the brain, forming intracranial myeloid sarcoma (MS), which presents a poor prognosis.
• * Limited drug penetration and resistance hinder effective treatment for brain leukemia.
• * Scarcity of intracranial MS tissue samples impedes understanding of leukemia cell behavior in the brain.

Purpose of the Study:

• * To develop a novel 3D in vitro model that accurately mimics the microenvironment of intracranial myeloid sarcoma.
• * To investigate the phenotypic alterations of leukemia cells within the brain parenchyma.
• * To identify key mechanisms contributing to treatment resistance and disease progression in intracranial MS.

Main Methods:

• * A 3D in vitro model was created using a hydrogel scaffold from decellularized brain extracellular matrix.
• * Leukemia cells were embedded within the scaffold to simulate tumor mass formation in the brain parenchyma.
• * Phenotypic changes, including cell survival, proliferation, differentiation, cell cycle, and gene expression, were analyzed.

Main Results:

• * The 3D model demonstrated significant phenotypic changes in leukemia cells, affecting survival, proliferation, and differentiation.
• * An increase in dormant leukemia stem cells and upregulation of multidrug resistance genes were observed, leading to imatinib resistance.
• * Suppression of ferroptosis was identified as a critical feature of intracranial MS, consistent with in vivo findings.

Conclusions:

• * The novel 3D in vitro model effectively replicates key pathological features of intracranial MS.
• * The study identified leukemia stem cell dormancy, multidrug resistance, and ferroptosis suppression as crucial for intracranial MS progression.
• * Findings provide valuable insights for developing targeted therapeutic strategies against brain leukemia.