{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:50:08Z","timestamp":1784307008997,"version":"3.55.0"},"reference-count":106,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Newcastle"},{"name":"Australian Government Research Training Program Scholarship (Academic Career Pathway Scheme)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite significant advancements in understanding the pathogenesis and treatment of hematological malignancies, including leukemia and multiple myeloma, the majority of patients continue to experience poor long-term outcomes. This is partly due to the difficulty of accurately recapitulating the malignant microenvironment in vitro, particularly the bone marrow niche. The complexity of the bone marrow microenvironment poses a challenge for the in vitro examination of hematological malignancies. Traditionally, 2D culture and animal models have been utilized, but these representations are limited and have been criticized for their lack of human physiological relevance. In an attempt to overcome this, 3D models have been developed that more accurately recapitulate the in vivo microenvironment. Herein, we present an overview of recent developments in 2D and 3D models used for studying the bone marrow niche in hematological malignancies, highlighting their advantages and limitations.<\/jats:p>","DOI":"10.3390\/cancers17152571","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T16:41:54Z","timestamp":1754325714000},"page":"2571","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Modeling the Bone Marrow Microenvironment to Better Understand the Pathogenesis, Progression, and Treatment of Hematological Cancers"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-3417","authenticated-orcid":false,"given":"Kathryn A.","family":"Skelding","sequence":"first","affiliation":[{"name":"Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW 2308, Australia"},{"name":"Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Barry","sequence":"additional","affiliation":[{"name":"Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW 2308, Australia"},{"name":"Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1612-2382","authenticated-orcid":false,"given":"Lisa F.","family":"Lincz","sequence":"additional","affiliation":[{"name":"Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW 2308, Australia"},{"name":"Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia"},{"name":"Hunter Haematology Research Group, Calvary Mater Hospital Newcastle, Newcastle, NSW 2298, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Epidemiology of Hematologic Malignancies in Real-World Settings: Findings from the Hemato-Oncology Latin America Observational Registry Study","volume":"5","author":"Chiattone","year":"2019","journal-title":"J. Glob. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3810","DOI":"10.1182\/blood-2023-187856","article-title":"Projected Global Trends in Hematological Malignancies: Incidence, Mortality, and Disability-Adjusted Life Years from 2020 to 2030","volume":"142","author":"An","year":"2023","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Skelding, K.A., Barry, D.L., Theron, D.Z., and Lincz, L.F. (2022). Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010563"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"jcs25072","DOI":"10.1242\/jcs.250720","article-title":"Characterization of Human Bone Marrow Niches with Metabolome and Transcriptome Profiling","volume":"134","author":"Ayhan","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature07434","article-title":"Live-Animal Tracking of Individual Haematopoietic Stem\/Progenitor Cells in Their Niche","volume":"457","author":"Fleming","year":"2009","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature11885","article-title":"Haematopoietic Stem Cells and Early Lymphoid Progenitors Occupy Distinct Bone Marrow Niches","volume":"495","author":"Ding","year":"2013","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nature13034","article-title":"Direct Measurement of Local Oxygen Concentration in the Bone Marrow of Live Animals","volume":"508","author":"Spencer","year":"2014","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s00424-016-1797-6","article-title":"The Impact of Chronic Intermittent Hypoxia on Hematopoiesis and the Bone Marrow Microenvironment","volume":"468","author":"Remedio","year":"2016","journal-title":"Pflugers. Arch."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ren, J., Szombath, G., Vitale-Cross, L., Stroncek, D.F., Robey, P.G., Hajdara, A., Szalayova, I., Mayer, B., Martin, D., and Mezey, E. (2023). The Potential Use of Thp-1, a Monocytic Leukemia Cell Line, to Predict Immune-Suppressive Potency of Human Bone-Marrow Stromal Cells (Bmscs) in Vitro: A Pilot Study. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713258"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1182\/hematology.2022000350","article-title":"Targeting Inflammation in Lower-Risk Mds","volume":"2022","author":"Verma","year":"2022","journal-title":"Hematology Am. Soc. Hematol. Educ. Program."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e152673","DOI":"10.1172\/JCI152673","article-title":"Bone Marrow-Confined Il-6 Signaling Mediates the Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia","volume":"132","author":"Mei","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s43018-020-0053-3","article-title":"Single-Cell Rna Sequencing Reveals Compromised Immune Microenvironment in Precursor Stages of Multiple Myeloma","volume":"1","author":"Zavidij","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ccell.2020.08.019","article-title":"Immunogenomic Landscape of Hematological Malignancies","volume":"38","author":"Dufva","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Aasebo, E., Brenner, A.K., Birkeland, E., Tvedt, T.H.A., Selheim, F., Berven, F.S., and Bruserud, O. (2021). The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells-a Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells. Cancers, 13.","DOI":"10.3390\/cancers13071509"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/cbf.3388","article-title":"Reciprocal Modulation of Cell Functions Upon Direct Interaction of Adipose Mesenchymal Stromal and Activated Immune Cells","volume":"37","author":"Bobyleva","year":"2019","journal-title":"Cell Biochem. Funct."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vanegas, N.P., Ruiz-Aparicio, P.F., Uribe, G.I., Linares-Ballesteros, A., and Vernot, J.P. (2021). Leukemia-Induced Cellular Senescence and Stemness Alterations in Mesenchymal Stem Cells Are Reversible Upon Withdrawal of B-Cell Acute Lymphoblastic Leukemia Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158166"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3864948","DOI":"10.1155\/2019\/3864948","article-title":"Acute Leukemia Induces Senescence and Impaired Osteogenic Differentiation in Mesenchymal Stem Cells Endowing Leukemic Cells with Functional Advantages","volume":"2019","author":"Bonilla","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1182\/blood-2018-04-845420","article-title":"Acute Myeloid Leukemia Induces Protumoral P16ink4a-Driven Senescence in the Bone Marrow Microenvironment","volume":"133","author":"Sun","year":"2019","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"de Oliveira, T.D., Vom Stein, A., Rebollido-Rios, R., Lobastova, L., Lettau, M., Janssen, O., Wagle, P., Nguyen, P.H., Hallek, M., and Hansen, H.P. (2022). Stromal Cells Support the Survival of Human Primary Chronic Lymphocytic Leukemia (Cll) Cells through Lyn-Driven Extracellular Vesicles. Front. Med., 9.","DOI":"10.3389\/fmed.2022.1059028"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1186\/s12967-023-04464-1","article-title":"Bm-Mscs Display Altered Gene Expression Profiles in B-Cell Acute Lymphoblastic Leukemia Niches and Exert Pro-Proliferative Effects Via Overexpression of Ifi6","volume":"21","author":"Pan","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1038\/s41467-023-36824-2","article-title":"Lyn Kinase Programs Stromal Fibroblasts to Facilitate Leukemic Survival Via Regulation of C-Jun and Thbs1","volume":"14","author":"Lukas","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.jcyt.2022.11.003","article-title":"Mesenchymal Stem\/Stromal Cells from a Transplanted, Asymptomatic Patient with Fanconi Anemia Exhibit an Aging-Like Phenotype and Dysregulated Expression of Genes Implicated in Hematopoiesis and Myelodysplasia","volume":"25","author":"Haga","year":"2023","journal-title":"Cytotherapy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1182\/blood.2024024818","article-title":"Il-1r1 and Il-18 Signals Regulate Mesenchymal Stromal Cells in an Aged Murine Model of Myelodysplastic Syndromes","volume":"145","author":"Kawano","year":"2025","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.celrep.2021.109119","article-title":"Integrated Omics Unveil the Bone-Marrow Microenvironment in Human Leukemia","volume":"35","author":"Passaro","year":"2021","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e359","DOI":"10.1038\/bcj.2015.85","article-title":"Alterations in Bone Marrow Metabolism Are an Early and Consistent Feature during the Development of Mgus and Multiple Myeloma","volume":"5","author":"Ludwig","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1182\/blood-2017-09-805499","article-title":"Extracellular Vesicle-Mediated Transfer of Constitutively Active Myd88(L265p) Engages Myd88(Wt) and Activates Signaling","volume":"131","author":"Lainscek","year":"2018","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6608","DOI":"10.1182\/bloodadvances.2022008268","article-title":"The Bone Marrow Stroma in Human Myelodysplastic Syndrome Reveals Alterations That Regulate Disease Progression","volume":"7","author":"Kfoury","year":"2023","journal-title":"Blood Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1182\/blood-2016-10-696005","article-title":"Myeloproliferative Neoplasm Stem Cells","volume":"129","author":"Mead","year":"2017","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sandberg, R., and Ernberg, I. (2005). The Molecular Portrait of in Vitro Growth by Meta-Analysis of Gene-Expression Profiles. Genome Biol., 6.","DOI":"10.1186\/gb-2005-6-8-r65"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/73432","article-title":"Systematic Variation in Gene Expression Patterns in Human Cancer Cell Lines","volume":"24","author":"Ross","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Le, V.H., Lee, S., Lee, S., Wang, T., Jang, W.H., Yoon, Y., Kwon, S., Kim, H., Lee, S.W., and Kim, K.H. (2017). In Vivo Longitudinal Visualization of Bone Marrow Engraftment Process in Mouse Calvaria Using Two-Photon Microscopy. Sci. Rep., 7.","DOI":"10.1038\/srep44097"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1038\/s41467-018-04770-z","article-title":"Quantitative Spatial Analysis of Haematopoiesis-Regulating Stromal Cells in the Bone Marrow Microenvironment by 3d Microscopy","volume":"9","author":"Gomariz","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-0716-1060-2_15","article-title":"Intravital 2-Photon Microscopy of Diverse Cell Types in the Murine Tibia","volume":"2236","author":"Hasenberg","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/nm.4103","article-title":"A Humanized Bone Marrow Ossicle Xenotransplantation Model Enables Improved Engraftment of Healthy and Leukemic Human Hematopoietic Cells","volume":"22","author":"Reinisch","year":"2016","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1182\/blood-2016-05-719021","article-title":"Establishing Human Leukemia Xenograft Mouse Models by Implanting Human Bone Marrow-Like Scaffold-Based Niches","volume":"128","author":"Antonelli","year":"2016","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1172\/JCI89364","article-title":"Versatile Humanized Niche Model Enables Study of Normal and Malignant Human Hematopoiesis","volume":"127","author":"Abarrategi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2114227118","DOI":"10.1073\/pnas.2114227118","article-title":"Culturing Patient-Derived Malignant Hematopoietic Stem Cells in Engineered and Fully Humanized 3d Niches","volume":"118","author":"Klein","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1073\/pnas.1222878110","article-title":"Genomic Responses in Mouse Models Poorly Mimic Human Inflammatory Diseases","volume":"110","author":"Seok","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41586-019-1104-8","article-title":"The Bone Marrow Microenvironment at Single-Cell Resolution","volume":"569","author":"Tikhonova","year":"2019","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1182\/blood.V89.2.376","article-title":"Altered Myeloid Development and Acute Leukemia in Transgenic Mice Expressing Pml-Rar Alpha under Control of Cathepsin G Regulatory Sequences","volume":"89","author":"Grisolano","year":"1997","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1182\/blood.V93.5.1707.405k24_1707_1714","article-title":"Tel\/Pdgfbetar Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor","volume":"93","author":"Tomasson","year":"1999","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1182\/blood.V96.6.2108","article-title":"Analysis of the Role of Aml1-Eto in Leukemogenesis, Using an Inducible Transgenic Mouse Model","volume":"96","author":"Rhoades","year":"2000","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100097","DOI":"10.1016\/j.xpro.2020.100097","article-title":"Co-Culture Systems of Drug-Treated Acute Myeloid Leukemia Cells and T Cells for in Vitro and in Vivo Study","volume":"1","author":"Li","year":"2020","journal-title":"STAR Protoc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1038\/s41467-018-04150-7","article-title":"A Retinoic Acid-Dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression","volume":"9","author":"Farinello","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.3324\/haematol.2016.162230","article-title":"High-Throughput Profiling of Signaling Networks Identifies Mechanism-Based Combination Therapy to Eliminate Microenvironmental Resistance in Acute Myeloid Leukemia","volume":"102","author":"Zeng","year":"2017","journal-title":"Haematologica"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47465","DOI":"10.18632\/oncotarget.10167","article-title":"Activation of Protein Phosphatase 2a in Flt3+ Acute Myeloid Leukemia Cells Enhances the Cytotoxicity of Flt3 Tyrosine Kinase Inhibitors","volume":"7","author":"Smith","year":"2016","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.2147\/CMAR.S167036","article-title":"Direct Comparison of Five Serum Biomarkers in Early Diagnosis of Hepatocellular Carcinoma","volume":"10","author":"Chen","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s12185-009-0392-4","article-title":"Long-Term Culture of Leukemic Bone Marrow Primary Cells in Biomimetic Osteoblast Niche","volume":"90","author":"Hou","year":"2009","journal-title":"Int. J. Hematol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bam, R., Khan, S., Ling, W., Randal, S.S., Li, X., Barlogie, B., Edmondson, R., and Yaccoby, S. (2015). Primary Myeloma Interaction and Growth in Coculture with Healthy Donor Hematopoietic Bone Marrow. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1892-7"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4139","DOI":"10.1038\/s41467-024-47793-5","article-title":"Bone Marrow Stromal Cells Induce Chromatin Remodeling in Multiple Myeloma Cells Leading to Transcriptional Changes","volume":"15","author":"Binder","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1007\/s00262-020-02728-z","article-title":"Anti-Leukemia Effect Associated with down-Regulated Cd47 and up-Regulated Calreticulin by Stimulated Macrophages in Co-Culture","volume":"70","author":"Hassan","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Nishi, M., Tateishi, K., Sundararaj, J.S., Ino, Y., Nakai, Y., Hatayama, Y., Yamaoka, Y., Mihana, Y., Miyakawa, K., and Kimura, H. (2023). Development of a Contacting Transwell Co-Culture System for the in Vitro Propagation of Primary Central Nervous System Lymphoma. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1275519"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/bph.16028","article-title":"Stromal Bone Marrow Fibroblasts and Mesenchymal Stem Cells Support Acute Myeloid Leukaemia Cells and Promote Therapy Resistance","volume":"181","author":"Miari","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Adamo, A., Delfino, P., Gatti, A., Bonato, A., Kamga, P.T., Bazzoni, R., Ugel, S., Mercuri, A., Caligola, S., and Krampera, M. (2020). Hs-5 and Hs-27a Stromal Cell Lines to Study Bone Marrow Mesenchymal Stromal Cell-Mediated Support to Cancer Development. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.584232"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Narazaki, A., Shimizu, R., Yoshihara, T., Kikuta, J., Sakaguchi, R., Tobita, S., Mori, Y., Ishii, M., and Nishikawa, K. (2022). Determination of the Physiological Range of Oxygen Tension in Bone Marrow Monocytes Using Two-Photon Phosphorescence Lifetime Imaging Microscopy. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-07521-9"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/febs.17263","article-title":"The Axl Inhibitor Bemcentinib Overcomes Microenvironment-Mediated Resistance to Pioglitazone in Acute Myeloid Leukemia","volume":"292","author":"Zhu","year":"2025","journal-title":"FEBS J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/S0301-472X(01)00612-9","article-title":"Acute Myeloid Leukemia Cells Are Protected from Spontaneous and Drug-Induced Apoptosis by Direct Contact with a Human Bone Marrow Stromal Cell Line (Hs-5)","volume":"29","author":"Garrido","year":"2001","journal-title":"Exp. Hematol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1038\/sj.leu.2402608","article-title":"Stromal Cells Prevent Apoptosis of Aml Cells by up-Regulation of Anti-Apoptotic Proteins","volume":"16","author":"Konopleva","year":"2002","journal-title":"Leukemia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1083\/jcb.200306090","article-title":"Polarity and Proliferation Are Controlled by Distinct Signaling Pathways Downstream of Pi3-Kinase in Breast Epithelial Tumor Cells","volume":"164","author":"Liu","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5061","DOI":"10.1182\/blood-2001-12-0290","article-title":"Augmentation of Umbilical Cord Blood (Ucb) Transplantation with Ex Vivo-Expanded Ucb Cells: Results of a Phase 1 Trial Using the Aastromreplicell System","volume":"101","author":"Jaroscak","year":"2003","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1158\/0008-5472.CAN-15-2402","article-title":"A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found in Vivo","volume":"76","author":"Hubert","year":"2016","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Cavo, M., Caria, M., Pulsoni, I., Beltrame, F., Fato, M., and Scaglione, S. (2018). A New Cell-Laden 3d Alginate-Matrigel Hydrogel Resembles Human Breast Cancer Cell Malignant Morphology, Spread and Invasion Capability Observed \u201cin Vivo\u201d. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-23250-4"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1182\/blood.2024024781","article-title":"Targeting Caseinolytic Mitochondrial Matrix Peptidase, a Novel Contributor to the Pathobiology of High-Risk Multiple Myeloma","volume":"145","author":"Qin","year":"2025","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/s41592-024-02172-2","article-title":"Generation of Complex Bone Marrow Organoids from Human Induced Pluripotent Stem Cells","volume":"21","author":"Fairley","year":"2024","journal-title":"Nat. Methods"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1158\/2159-8290.CD-22-0199","article-title":"Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies","volume":"13","author":"Khan","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e1434465","DOI":"10.1080\/2162402X.2018.1434465","article-title":"Cellular Immunotherapy on Primary Multiple Myeloma Expanded in a 3d Bone Marrow Niche Model","volume":"7","author":"Braham","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.biomaterials.2015.09.017","article-title":"3d Tissue-Engineered Bone Marrow as a Novel Model to Study Pathophysiology and Drug Resistance in Multiple Myeloma","volume":"73","author":"Muz","year":"2015","journal-title":"Biomaterials"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e2401192","DOI":"10.1002\/adhm.202401192","article-title":"T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3k9me3 Modifications","volume":"14","author":"Britto","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41563-023-01495-3","article-title":"Combinatorial Treatment Rescues Tumour-Microenvironment-Mediated Attenuation of Malt1 Inhibitors in B-Cell Lymphomas","volume":"22","author":"Shah","year":"2023","journal-title":"Nat. Mater."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.3324\/haematol.2018.211904","article-title":"Daratumumab Displays in Vitro and in Vivo Anti-Tumor Activity in Models of B-Cell Non-Hodgkin Lymphoma and Improves Responses to Standard Chemo-Immunotherapy Regimens","volume":"105","author":"Rodriguez","year":"2020","journal-title":"Haematologica"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.stem.2024.01.012","article-title":"A Human Lymphoma Organoid Model for Evaluating and Targeting the Follicular Lymphoma Tumor Immune Microenvironment","volume":"31","author":"Kastenschmidt","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e007156","DOI":"10.1136\/jitc-2023-007156","article-title":"Patient-Derived Lymphoma Spheroids Integrating Immune Tumor Microenvironment as Preclinical Follicular Lymphoma Models for Personalized Medicine","volume":"11","author":"Faria","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41563-024-02037-1","article-title":"Human Immune Organoids to Decode B Cell Response in Healthy Donors and Patients with Lymphoma","volume":"24","author":"Zhong","year":"2025","journal-title":"Nat. Mater."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ceccato, J., Piazza, M., Pizzi, M., Manni, S., Piazza, F., Caputo, I., Cinetto, F., Pisoni, L., Trojan, D., and Scarpa, R. (2022). A Bone-Based 3D Scaffold as an in-Vitro Model of Microenvironment-Dlbcl Lymphoma Cell Interaction. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.947823"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Balandran, J.C., Davila-Velderrain, J., Sandoval-Cabrera, A., Zamora-Herrera, G., Teran-Cerqueda, V., Garcia-Stivalet, L.A., Limon-Flores, J.A., Armenta-Castro, E., Rodriguez-Martinez, A., and Leon-Chavez, B.A. (2021). Patient-Derived Bone Marrow Spheroids Reveal Leukemia-Initiating Cells Supported by Mesenchymal Hypoxic Niches in Pediatric B-All. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.746492"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"103103","DOI":"10.1016\/j.xpro.2024.103103","article-title":"Protocol for in Vitro Co-Culture Assay for Rapid Expansion of Human T Cell Acute Lymphoblastic Leukemia","volume":"5","author":"Rivera","year":"2024","journal-title":"STAR Protoc."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.3324\/haematol.2020.248112","article-title":"Three-Dimensional Co-Culture Model of Chronic Lymphocytic Leukemia Bone Marrow Microenvironment Predicts Patient-Specific Response to Mobilizing Agents","volume":"106","author":"Barbaglio","year":"2021","journal-title":"Haematologica"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ferrarini, M., Steimberg, N., Ponzoni, M., Belloni, D., Berenzi, A., Girlanda, S., Caligaris-Cappio, F., Mazzoleni, G., and Ferrero, E. (2013). Ex-Vivo Dynamic 3-D Culture of Human Tissues in the Rccs Bioreactor Allows the Study of Multiple Myeloma Biology and Response to Therapy. PLoS ONE, 8.","DOI":"10.1371\/annotation\/d7d8e0a7-aa3d-4620-98e5-c5a7bbf31dc8"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Santos Rosalem, G., Torres, L.A.G., de Las Casas, E.B., Mathias, F.A.S., Ruiz, J.C., and Carvalho, M.G.R. (2020). Microfluidics and Organ-on-a-Chip Technologies: A Systematic Review of the Methods Used to Mimic Bone Marrow. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0243840"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"David, R., Gee, S., Khan, K., Wilson, A., and Doherty, A. (2021). Three Dimensional and Microphysiological Bone Marrow Models Detect in Vivo Positive Compounds. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-01400-5"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"eaba5536","DOI":"10.1126\/sciadv.aba5536","article-title":"Leukemia-on-a-Chip: Dissecting the Chemoresistance Mechanisms in B Cell Acute Lymphoblastic Leukemia Bone Marrow Niche","volume":"6","author":"Ma","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_82","first-page":"113","article-title":"Growth of Multicell Spheroids in Tissue Culture as a Model of Nodular Carcinomas","volume":"46","author":"Sutherland","year":"1971","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.bone.2018.01.023","article-title":"Development of a 3D Bone Marrow Adipose Tissue Model","volume":"118","author":"Fairfield","year":"2019","journal-title":"Bone"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1002\/jbmr.4404","article-title":"A Functional Three-Dimensional Microphysiological Human Model of Myeloma Bone Disease","volume":"36","author":"Visconti","year":"2021","journal-title":"J. Bone Miner. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"8105","DOI":"10.2147\/IJN.S184262","article-title":"Liposomal Drug Delivery in an in Vitro 3d Bone Marrow Model for Multiple Myeloma","volume":"13","author":"Braham","year":"2018","journal-title":"Int. J. Nanomedicine"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1182\/bloodadvances.2024013361","article-title":"Development of Ipsc-Derived Human Bone Marrow Organoid for Autonomous Hematopoiesis and Patient-Derived Hspc Engraftment","volume":"9","author":"Ren","year":"2025","journal-title":"Blood Adv."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Rellick, S.L., Hu, G., Piktel, D., Martin, K.H., Geldenhuys, W.J., Nair, R.R., and Gibson, L.F. (2021). Co-Culture Model of B-Cell Acute Lymphoblastic Leukemia Recapitulates a Transcription Signature of Chemotherapy-Refractory Minimal Residual Disease. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-95039-x"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3109\/10428194.2013.793323","article-title":"A Novel Three-Dimensional Stromal-Based Model for in Vitro Chemotherapy Sensitivity Testing of Leukemia Cells","volume":"55","author":"Aljitawi","year":"2014","journal-title":"Leuk Lymphoma"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1089\/ten.tec.2016.0404","article-title":"Mimicking the Acute Myeloid Leukemia Niche for Molecular Study and Drug Screening","volume":"23","author":"Houshmand","year":"2017","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.3324\/haematol.2016.157883","article-title":"A Three-Dimensional Ex Vivo Tri-Culture Model Mimics Cell-Cell Interactions between Acute Myeloid Leukemia and the Vascular Niche","volume":"102","author":"Bray","year":"2017","journal-title":"Haematologica"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Cheung, H.L., Wong, Y.H., Li, Y.Y., Yang, X., Ko, L.H., Kabigting, J.E.T., Chan, K.C., Leung, A.Y.H., and Chan, B.P. (2025). Microenvironment Matters: In Vitro 3D Bone Marrow Niches Differentially Modulate Survival, Phenotype and Drug Responses of Acute Myeloid Leukemia (Aml) Cells. Biomaterials, 312.","DOI":"10.1016\/j.biomaterials.2024.122719"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.cell.2006.06.044","article-title":"Matrix Elasticity Directs Stem Cell Lineage Specification","volume":"126","author":"Engler","year":"2006","journal-title":"Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.biomaterials.2015.09.007","article-title":"Integrin-Specific Hydrogels as Adaptable Tumor Organoids for Malignant B and T Cells","volume":"73","author":"Tian","year":"2015","journal-title":"Biomaterials"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6987","DOI":"10.1016\/j.biomaterials.2012.06.029","article-title":"Cord Blood-Hematopoietic Stem Cell Expansion in 3D Fibrin Scaffolds with Stromal Support","volume":"33","author":"Ferreira","year":"2012","journal-title":"Biomaterials"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Severn, C.E., Macedo, H., Eagle, M.J., Rooney, P., Mantalaris, A., and Toye, A.M. (2016). Polyurethane Scaffolds Seeded with Cd34(+) Cells Maintain Early Stem Cells Whilst Also Facilitating Prolonged Egress of Haematopoietic Progenitors. Sci. Rep., 6.","DOI":"10.1038\/srep32149"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1023\/A:1008157303025","article-title":"The Construction of an in Vitro Three-Dimensional Hematopoietic Microenvironment for Mouse Bone Marrow Cells Employing Porous Carriers","volume":"34","author":"Tomimori","year":"2000","journal-title":"Cytotechnology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.biomaterials.2013.10.038","article-title":"Biomimetic Macroporous Peg Hydrogels as 3d Scaffolds for the Multiplication of Human Hematopoietic Stem and Progenitor Cells","volume":"35","author":"Raic","year":"2014","journal-title":"Biomaterials"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.3892\/ijmm.2016.2712","article-title":"Three-Dimensional Co-Culture of Mesenchymal Stromal Cells and Differentiated Osteoblasts on Human Bio-Derived Bone Scaffolds Supports Active Multi-Lineage Hematopoiesis in Vitro: Functional Implication of the Biomimetic Hsc Niche","volume":"38","author":"Huang","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/j.biomaterials.2011.11.034","article-title":"3D Co-Culture of Hematopoietic Stem and Progenitor Cells and Mesenchymal Stem Cells in Collagen Scaffolds as a Model of the Hematopoietic Niche","volume":"33","author":"Leisten","year":"2012","journal-title":"Biomaterials"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1038\/s41591-019-0601-5","article-title":"Expansion of Primitive Human Hematopoietic Stem Cells by Culture in a Zwitterionic Hydrogel","volume":"25","author":"Bai","year":"2019","journal-title":"Nat. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"E5688","DOI":"10.1073\/pnas.1805440115","article-title":"In Vitro Biomimetic Engineering of a Human Hematopoietic Niche with Functional Properties","volume":"115","author":"Bourgine","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Krater, M., Jacobi, A., Otto, O., Tietze, S., Muller, K., Poitz, D.M., Palm, S., Zinna, V.M., Biehain, U., and Wobus, M. (2017). Bone Marrow Niche-Mimetics Modulate Hspc Function Via Integrin Signaling. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-02352-5"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1039\/C8BM01503A","article-title":"Characterization of a Novel Decellularized Bone Marrow Scaffold as an Inductive Environment for Hematopoietic Stem Cells","volume":"7","author":"Bianco","year":"2019","journal-title":"Biomater. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7060","DOI":"10.1016\/j.biomaterials.2011.06.008","article-title":"The Effect of Decellularized Bone\/Bone Marrow Produced by High-Hydrostatic Pressurization on the Osteogenic Differentiation of Mesenchymal Stem Cells","volume":"32","author":"Hashimoto","year":"2011","journal-title":"Biomaterials"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.leukres.2018.08.012","article-title":"A Novel Extracellular Matrix-Based Leukemia Model Supports Leukemia Cells with Stem Cell-Like Characteristics","volume":"72","author":"Li","year":"2018","journal-title":"Leuk Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1089\/ten.tec.2013.0490","article-title":"Patient-Specific 3D Microfluidic Tissue Model for Multiple Myeloma","volume":"20","author":"Zhang","year":"2014","journal-title":"Tissue Eng. 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