Critical modulation of hematopoietic lineage fate by the PAR/bZIP transcription factor Hepatic Leukemia Factor

Blood cell formation is a tightly regulated process initiated from a rare population of multipotent hematopoietic stem cells. Subsequent differentiation proceeds in a hierarchical manner with the generation of intermediate progenitor cells, in which alternative lineage potentials become gradually restricted. A deeper understanding of these events is crucial not only to understand normal blood cell formation, but also for leukemia, where a defining feature is inappropriate differentiation. Here, we identified Hepatic Leukemia Factor (Hlf) as being highly and selectively expressed in primitive multipotent hematopoietic stem and progenitors. We demonstrate that Hlf is a strong negative regulator of B-, NK- and T cell development and instructs multipotent progenitors to adopt a myeloid fate in a cell autonomous manner; phenotypes underwritten by the induction of myeloid affiliated transcriptional programs, the concomitant ablation of lymphoid gene programs and genome-wide binding spectra that involved active enhancers of myeloid-competent cells. Collectively, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis. Identification of Hlf binding sites in Lin-Sca-1+c-Kit+ cells