Engineering autologous ossicles for the personalized modeling of acute myeloid leukemia

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Abstract Acute Myeloid Leukemia (AML) is the most lethal hematological malignancy in adults and is characterized by significant genetic and cytogenetic heterogeneity. This diversity drives substantial patient-to-patient variability in disease progression and therapeutic response. Increasing evidence indicates that bone marrow mesenchymal stem/stromal cells (MSCs) play a critical role in AML emergence, evolution and treatment resistance. However, progress in the field is challenged by the lack of experimental models supporting sustained AML survival while faithfully recapitulating the human bone marrow niche. Humanized ossicles (hOss) have recently emerged as ectopic human bone/bone marrow microenvironments composed of MSCs and hematopoietic elements, enabling improved AML engraftment i n vivo . Nonetheless, those models typically exploit healthy MSCs largely because primary patient-derived cells exhibit diminished ossification potential. Here, we introduce OssiGel, a novel engineered human cartilage extracellular matrix produced by a mesenchymal cell line. We hypothesized that combining OssiGel with primary MSCs would enable the robust formation of hOss in healthy and malignant settings. We report that OssiGel supports fast and reproducible formation of hOss through endochondral ossification using MSCs isolated from both healthy and AML bone marrow samples. Within hOss, AML-MSCs were shown to persist long-term and to generate a human stromal microenvironment supporting the establishment of autologous AML hematopoietic cells, enabling the generation of autologous (autologOss). Single-cell RNA sequencing (scRNA-seq) revealed that autologOss recapitulate the majority of the AML blood populations observed in the corresponding patient bone marrow samples. Moreover, proof-of-concept sequencing of AML-MSCs from autologOss allowed predictive interrogation of interactions with leukemic populations and revealed the acquisition of an inflammatory-like phenotype, characteristic of AML. Taken together, our study establishes OssiGel as a novel platform for the robust engineering of autologous ossicles from AML patient samples. This provides a relevant tool to decipher patient-specific cellular interactions and drug responses, with potential translational value to broad hematological malignancies.

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