Aberrant stem cell and developmental programs in pediatric leukemia.

Hematopoiesis is a finely orchestrated process, whereby hematopoietic stem cells give rise to all mature blood cells. Crucially, they maintain the ability to self-renew and/or differentiate to replenish downstream progeny. This process starts at an embryonic stage and continues throughout the human lifespan. Blood cancers such as leukemia occur when normal hematopoiesis is disrupted, leading to uncontrolled proliferation and a block in differentiation of progenitors of a particular lineage (myeloid or lymphoid). Although normal stem cell programs are crucial for tissue homeostasis, these can be co-opted in many cancers, including leukemia. Myeloid or lymphoid leukemias often display stem cell-like properties that not only allow proliferation and survival of leukemic blasts but also enable them to escape treatments currently employed to treat patients. In addition, some leukemias, especially in children, have a fetal stem cell profile, which may reflect the developmental origins of the disease. Aberrant fetal stem cell programs necessary for leukemia maintenance are particularly attractive therapeutic targets. Understanding how hijacked stem cell programs lead to aberrant gene expression in place and time, and drive the biology of leukemia, will help us develop the best treatment strategies for patients.

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.

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 TGFß 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. SIGNIFICANCE: 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.

The Origin of B-cells: Human Fetal B Cell Development and Implications for the Pathogenesis of Childhood Acute Lymphoblastic Leukemia.

Human B-lymphopoiesis is a dynamic life-long process that starts in utero by around six post-conception weeks. A detailed understanding of human fetal B-lymphopoiesis and how it changes in postnatal life is vital for building a complete picture of normal B-lymphoid development through ontogeny, and its relevance in disease. B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common cancers in children, with many of the leukemia-initiating events originating in utero. It is likely that the biology of B-ALL, including leukemia initiation, maintenance and progression depends on the developmental stage and type of B-lymphoid cell in which it originates. This is particularly important for early life leukemias, where specific characteristics of fetal B-cells might be key to determining how the disease behaves, including response to treatment. These cellular, molecular and/or epigenetic features are likely to change with age in a cell intrinsic and/or microenvironment directed manner. Most of our understanding of fetal B-lymphopoiesis has been based on murine data, but many recent studies have focussed on characterizing human fetal B-cell development, including functional and molecular assays at a single cell level. In this mini-review we will give a short overview of the recent advances in the understanding of human fetal B-lymphopoiesis, including its relevance to infant/childhood leukemia, and highlight future questions in the field.