02872nas a2200457   4500000000100000008004100001260001500042100002100057700002900078700002100107700002300128700002000151700001700171700001800188700002000206700002100226700002100247700001800268700002600286700002000312700002400332700003000356700002000386700001800406700002000424700002200444700001800466700001800484700003500502700001700537700001800554700001600572700002200588700001800610245013100628856004900759300001200808490000700820520157300827022001402400       2023                            d  c2023-02-061 aAbdullah O. Khan1 aAntonio Rodriguez-Romera1 aJasmeet S. Reyat1 aAude-Anais Olijnik1 aMichela Colombo1 aGuanlin Wang1 aWei Xiong Wen1 aNikolaos Sousos1 aLauren C. Murphy1 aBeata Grygielska1 aGina Perrella1 aChristopher B. Mahony1 aRebecca E. Ling1 aNatalina E. Elliott1 aChristina Simoglou Karali1 aAndrew P. Stone1 aSamuel Kemble1 aEmily A. Cutler1 aAdele K. Fielding1 aAdam P. Croft1 aDavid Bassett1 aGowsihan Poologasundarampillai1 aAnindita Roy1 aSarah Gooding1 aJulie Rayes1 aKellie R. Machlus1 aBethan Psaila00aHuman Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies  uhttps://doi.org/10.1158/2159-8290.CD-22-0199  a364-3850 v133 aA 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  a2159-8274