HOX genes in normal, engineered and malignant hematopoiesis.

Advanced technologies and models systems are improving our understanding of developmental processes. A primary example, hematopoiesis, classically represented by a hierarchical tree with a stem cell at the apex and more lineage restricted cells following each bifurcation has recently been shown to be capable of more adaptable fate decisions. Future research will identify key molecules underpinning this more adaptable or continuous model of hematopoiesis potentially leading to improved engineering of blood cells and therapies for malignant disease. The spatio-temporal, cell specific and exquisite reliance on gene dosage attributed to the HOX family promoted them as candidate master regulators of hierarchical hematopoiesis. Recent discoveries in the need to stimulate or retain HOX expression during engineered human hematopoiesis, supported by similar studies in mice and other developmental models, reinforces their importance at the single cell level. Likewise, dysregulation of HOX in single cells can result in blood cancers such as leukemia. It will be of interest to see what additional roles HOX family members and their regulators including morphogens, epigenetic modifiers and noncoding RNAs play in this evolving field and if these master regulators can be further harnessed for clinical benefit.