The JunB Transcriptional Network: from Hematopoietic Stem Cells to Myeloid Function.

Abstract

Abstract Hematopoietic development is organized hierarchically, starting with a rare population of hematopoietic stem cells (HSCs) that gives rise to a series of committed myeloid progenitors and mature cells with particular functional and immunophenotypic properties. HSCs are operationally defined by their ability to provide long-term multilineage reconstitution when transplanted into hematopoietically compromised recipient, and are the only cells within the myeloid series that self-renew throughout life. Under steady-state conditions, HSCs are largely quiescent, slowly cycling cells. However, in response to environmental stresses, HSCs can undergo dramatic expansion and contraction to ensure proper homeostatic replacement of blood cells. HSCs are found predominantly in the bone marrow (BM) associated with several recently described vascular and endosteal niches. A complex balance of cell extrinsic factors present in these niches maintains HSCs in relatively dormant states and regulate their trafficking to and from these BM microenvironments. Recent studies have highlighted the roles of specific signal transducer (Pten), polycomb group protein (Bmi1), transcription factors (JunB, Gfi-1, Hox genes), and extrinsic regulatory pathways (Notch, TGF-beta, Wnt) in controlling HSC selfrenewal, proliferation, and differentiation. Here, we will review the various experimental approaches used to identify and functionally assess HSC and myeloid progenitor activity in the mouse. We will discuss how HSCs are molecularly equipped to integrate signals from the microenvironment, and how such regulations control the balance between proliferation and early myeloid differentiation. The case of the JunB/AP-1 transcription factor will be used as an example of pathological situation. Inactivation of JunB leads to the development of a myloproliferative disease (MPD) arising from the HSC compartment. JunB normally controls HSC proliferation by regulating the expression levels of key cell cycle regulators, including Bmi1, and limits the rate at which HSCs produce early myeloid progenitors by maintaining appropriate responsiveness to both Notch and TGF-beta signaling pathways. The transforming effect of JunB loss is, therefore, due to a broad deregulation of the regulatory mechanisms controlling HSC differentiation, leading to overproduction of myeloid progenitors and MPD development in vivo. These results provide insights into fundamental issues in hematopoiesis and leukemogenesis.