SMART-AML · Shaping Marrow Adiposity to Redefine Treatment in Acute Myeloid Leukemia

SMART-AML: Shaping Marrow Adiposity to Redefine Treatment in Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled proliferation of myeloid cells, which hijack the bone marrow (BM) and compromise its physiological functions. AML prognosis remains poor, with <10% of patients above 60 years old surviving after 5 years. Recent discoveries have revealed the key role of the BM microenvironment in harboring and protecting leukemic stem cells from chemotherapy, contributing to AML relapse. Therefore, targeting the hijacked BM niche and transforming it into a “tumor-inhospitable” microenvironment represents a promising therapeutic strategy. In adults, bone marrow adipose tissue (BMAT) is the predominant component of the BM microenvironment, making it a potential target to render the niche inadequate for leukemic cells survival. Nevertheless, the role of BMAT in AML development, drug resistance, and survival are still controversial. The overall aim of SMART-AML was to identify AML cell-related changes within the BMAT/BM microenvironment and evaluate the potential of BMAT manipulation as a therapeutic strategy to sensitize leukemic cells to chemotherapy. To achieve this goal, the first focus was to exploit state-of-the-art bioprinting technologies to engineer a perfusable, humanized bone/BMAT 3D biomimetic microenvironment. Specifically, volumetric bioprinting was selected as the biofabrication technique because it allows the fabrication of cm3-scale constructs with complex geometries within seconds without compromising cell viability. To ensure the physiological relevance of the engineered BM environment model, it was initially evaluated whether the bioprinting process introduced any additional cellular stress or alteration in the cellular DNA, as such alterations could compromise the model’s baseline integrity, introducing artefactual changes and thereby limit the biological relevance of the system. Next, the biomaterials and bioprinting conditions for the engineering of the two different components of the BM, i.e. the bone and the BMAT, were selected. Finally, the model was completed by evaluating the attachment and survival of a blood cancer cell line in both compartments of the engineered BM niche. Future studies will focus on culturing patient-derived AML cells within the engineered platform to characterize the AML-induced BMAT changes in a controlled environment, with limited variables. By manipulating the BMAT it will be possible to determine the potential of this therapeutic approach to enhance the efficacy of chemotherapy on leukemic stem cells and reduce the chance of relapse. In addition to the value of the developed model for cancer research, the developed two-compartment platform could be used as a starting point for studying other pathological conditions where the relationship between bone and BMAT is key, such as osteoporosis.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз