Brain-decellularized ECM-based 3d Myeloid Sarcoma Platform: Mimicking Adaptive Phenotypic Alterations in The Brain.

Leukemia circulates in the bloodstream and induces various symptoms and complications. Occasionally, these cells accumulate in non-marrow tissues, forming a tumor-like myeloid sarcoma (MS). When the blast-stage leukemia cells invade the brain parenchyma, intracranial MS occurs, leading to a challenging prognosis owing to the limited penetration of cytostatic drugs into the brain and the development of drug resistance. The scarcity of tissue samples from MS makes understanding the phenotypic changes occurring in leukemia cells within the brain environment challenging, thereby hindering development of effective treatment strategies for intracranial MS. This study presents a novel three-dimensional in vitro model mimicking intracranial MS, employing a hydrogel scaffold derived from the brain-decellularized extracellular matrix in which suspended leukemia cells are embedded, simulating the formation of tumor masses in the brain parenchyma. This model revealed marked phenotypic changes in leukemia cells, including altered survival, proliferation, differentiation, and cell cycle regulation. Notably, proportion of dormant leukemia stem cells increased and expression of multidrug resistance genes was upregulated, leading to imatinib resistance, mirroring the pathological features of in vivo MS tissue. Furthermore, suppression of ferroptosis has been identified as an important characteristic of intracranial MS, providing valuable insights for the development of targeted therapeutic strategies. This article is protected by copyright. All rights reserved.