Abstract B003: In vitro 3D bone marrow niches differentially modulate survival, phenotype and drug responses of acute myeloid leukemia (AML) cells
Authors: Hoi Lam Cheung, Yu Hin Wong, Yuk Yin Li, Xing Xing Yang, Lok Him Ko, Jessica Evangeline Tan Kabigting, Koon Chuen Chan, Anskar Yu Hung Leung, B.P. Chan
Journal: Cancer Research (2024)

Abstract Introduction: Acute myeloid leukemia (AML) is the deadliest type of hematopoietic cancer, with only about 50% of patients achieving overall survival [1]. This poor treatment outcome may be attributed to the significant heterogeneity of AML. Personalized cancer drug screening could be a solution, but primary AML cells undergo spontaneous apoptosis in ex vivo cultures [2], making personalized drug screening challenging. Research has indicated that stromal cells and extracellular matrix (ECM) create a pro-tumoral environment to support AML cells. We hypothesized that the bone marrow microenvironment mimicked by osteolineage cells encapsulated in ECM called 3D osteogenic niche (3DON) would support the survival of primary AML cells, and the presence of a biomimetic 3D cancer microenvironment would provide more reliable screening outcomes. Methods: Our laboratory has been developing a 3D microencapsulation platform using naturally occurring ECM to fabricate physiologically relevant and ECM-based 3D microtissues. 3D osteogenic niche (3DON) which mimics that in bone marrow is fabricated to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. Results: The AML cells co-cultured with the AML 3DON niche demonstrated improved viability, decreased apoptosis and preserved their CD33+ CD34− phenotype, which associated with the increased secretion of anti-apoptotic cytokines in the AML 3DON niche. In addition, AML cells under the AML 3DON niche displayed reduced sensitivity to FDA-approved chemotherapeutic drugs, doxorubicin and daunorubicin, while being more chemosensitive in the healthy 3DON niche. This further suggests the physiological relevance of the AML 3DON niche. Discussion and Conclusion: The AML 3DON maintained the viability and phenotypes of primary AML cells, suggesting that the AML 3DON environment may be more biomimetic and hence may achieve more reliable drug screening results. This study highlights the differential responses of AML cells to leukemic versus healthy bone marrow niches, suggesting the influence of native cancer cell niche in drug screening. It also suggests the potential of re-engineering healthy bone marrow niche to overcome AML chemoresistance. References: 1) Bertoli, S., Tavitian, S., Huynh, A., Borel, C., Guenounou, S., Luquet, I., ... &amp; Récher, C. (2017). Improved outcome for AML patients over the years 2000–2014. Blood cancer journal, 7(12), 1-9. 2) Brenner, A. K., Aasebø, E., Hernandez-Valladares, M., Selheim, F., Berven, F., Grønningsæter, I. S., ... &amp; Bruserud, Ø. (2019). The capacity of long-term in vitro proliferation of acute myeloid leukemia cells supported only by exogenous cytokines is associated with a patient subset with adverse outcome. Cancers, 11(1), 73. Citation Format: Hoi Lam Cheung, Yu Hin Wong, Yuk Yin Li, Xing Xing Yang, Lok Him Ko, Jessica Evangeline Tan Kabigting, Koon Chuen Chan, Anskar Yu Hung Leung, B.P. Chan. In vitro 3D bone marrow niches differentially modulate survival, phenotype and drug responses of acute myeloid leukemia (AML) cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B003.