TY - JOUR
AU - Abdullah O. Khan
AU - Antonio Rodriguez-Romera
AU - Jasmeet S. Reyat
AU - Aude-Anais Olijnik
AU - Michela Colombo
AU - Guanlin Wang
AU - Wei Xiong Wen
AU - Nikolaos Sousos
AU - Lauren C. Murphy
AU - Beata Grygielska
AU - Gina Perrella
AU - Christopher B. Mahony
AU - Rebecca E. Ling
AU - Natalina E. Elliott
AU - Christina Simoglou Karali
AU - Andrew P. Stone
AU - Samuel Kemble
AU - Emily A. Cutler
AU - Adele K. Fielding
AU - Adam P. Croft
AU - David Bassett
AU - Gowsihan Poologasundarampillai
AU - Anindita Roy
AU - Sarah Gooding
AU - Julie Rayes
AU - Kellie R. Machlus
AU - Bethan Psaila
AB - A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow—stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers.We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.See related commentary by Derecka and Crispino, p. 263.This article is highlighted in the In This Issue feature, p. 247
BT - Cancer Discovery
DA - 2023-02-06
DO - 10.1158/2159-8290.CD-22-0199
IS - 2
N2 - A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow—stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers.We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.See related commentary by Derecka and Crispino, p. 263.This article is highlighted in the In This Issue feature, p. 247
PY - 2023
SP - 364
EP - 385
T2 - Cancer Discovery
TI - Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies
UR - https://doi.org/10.1158/2159-8290.CD-22-0199
VL - 13
Y2 - 2024-08-13
SN - 2159-8274
ER -