Riccardo Piussi

The hematopoietic system performs essential functions for living organisms through a wide array of cell types, including immune cells for host defense, erythrocytes for oxygen transport, and megakaryocytes involved in vascular and tissue repair. The adoptive transfer of mature blood cells and the transplantation of hematopoietic stem cells (HSCs) have been extensively exploited in clinical settings for the treatment of inherited blood disorders as well as blood malignancies. In addition, blood cells are also preferential targets in the context of gene therapy, in which they provide revolutionary treatments not only for classical hematologic diseases but also for novel and unexpected indications, such as inherited metabolic disorders. However, clinical bottlenecks remain, including the limited availability of suitably matched donor cells, the need for high cell doses, and the complexity of personalized manufacturing. Given their proliferative ability and capacity to generate any human cell type, human pluripotent stem cells (hPSCs), encompassing both embryonic stem cells (ESCs) and induced PSCs, represent a novel, potentially unlimited, easy-to-engineer source of either patient-specific or allogeneic blood cells for “off-the-shelf” cell therapies. In parallel, hPSC-derived blood cells enable in vitro modeling of diverse hematologic diseases and the identification of novel therapeutic targets. Recent advances describing protocols for the de novo generation of HSCs are opening new and exciting avenues for a broad application of hPSC-derived blood cells in both basic research and clinical medicine.

Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem cell gene regulatory programs, but the mechanisms through which these programs are propogated remain poorly understood. The increased expression of the stem cell transcription factor, MECOM, underlies a key driver mechanism in largely incurable AMLs. However, how MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell–like states by directly repressing prodifferentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kilobase (kb) downstream of the myeloid differentiation regulator CEBPA is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, the targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. These findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.