The mammalian hematopoietic system provides a unique, tractable model for investigating how cancer-associated mutations affect the behavior of specific cell populations and lead to the development of blood cancer or leukemia (Orkin and Zon, 2008
). Hematopoietic development is organized hierarchically, starting with a rare population of hematopoietic stem cells (HSCs) that gives rise to a series of committed 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 recipients, and are the only cells that self-renew throughout life. HSCs are found predominantly in the bone marrow (BM) associated with several recently described vascular and endosteal niches (Kiel and Morrison, 2008
). A complex balance of cell intrinsic regulators and cell extrinsic factors present in these niches normally maintain HSCs in a state of relative dormancy and regulate their trafficking to and from these BM niches. Under steady-state conditions, HSCs are a largely quiescent, slowly cycling cell population, which, in response to environmental stresses, are capable of dramatic expansion and contraction to ensure proper homeostatic replacement of blood cells (Passegué et al., 2005
Gene knockout studies in mice have demonstrated that regulation of HSC numbers can be accomplished through direct modulation of HSC proliferative activity, resistance to apoptosis and retention in the BM niches (Orkin and Zon, 2008
). Important mediators of these processes include cell cycle regulators such as the D-cyclins and the cyclin-dependant kinase inhibitors (CKIs) p21/CIP1 and p18/INK4c. Recent studies have also highlighted the roles of specific signal transducer (Pten), transcription factors (Gfi1, HoxB4, HoxA9) and extrinsic regulatory pathways (Notch, TGF-β, Wnt) in controlling HSC self-renewal and proliferation (Akala and Clarke, 2006
; Blank et al., 2008
). However, the precise molecular circuitry controlling HSC fate decisions has yet to be fully elucidated, and the mechanisms by which HSC maintenance, proliferation and differentiation are coordinately regulated to ensure homeostatic production of blood cells remain poorly understood. Recently, it has been suggested that changes in the quiescence status of HSCs (Holyoake et al., 1999
) and deregulation of their interaction with BM niches (Jin et al., 2006
) could be key events for their leukemic transformation and the development of myeloid leukemia. Still, little is known about the impact of leukemic transformation on HSC biological function and how abnormal HSC-derived leukemia-initiating stem cells (LSCs) differ from normal HSCs.
Originally discovered in leukemia, cancer-initiating stem cells have now been recognized in a variety of solid tumors (Wang and Dick, 2005
). They represent a subset of a heterogeneous cancer population and are operationally defined by their ability to drive the formation and growth of a new tumor in transplanted mice. Convincing evidence indicates that LSCs are inefficiently eliminated by current therapeutic treatments and suggests that LSC persistence could be responsible for disease maintenance and/or recurrence (Jordan et al., 2006
). Developing therapeutic interventions that specifically target LSCs is an appealing strategy for improving leukemia treatment, which requires an understanding of how LSCs escape normal regulatory mechanisms and become malignant. Few mouse models of human leukemia are currently available in which the LSC population has been identified and can be purified for analysis (Wang and Dick, 2005
). This is an essential prerequisite for identifying pathways and molecules available for interventional therapies in patients.
We have previously developed several mouse strains lacking the JunB/AP-1 transcription factor that accurately recapitulate important clinical aspects of human myeloid malignancies, including chronic myelogenous leukemia (CML) (Passegué et al., 2001
). We have also identified the LSC population as arising from the HSC compartment during the pre-cancerous myeloproliferative disease (MPD) phase (Passegué et al., 2004
). Importantly, JunB inactivation has been observed in a spectrum of human myeloid malignancies, including CML (Yang et al., 2003
), and downregulation of jun
B expression has been found in the HSC compartment of patients with acute myeloid leukemia (Steidl et al., 2006
). At present, little is known about the role of JunB in HSC biology and myeloid leukemia development. Here, we have used jun
B-deficient mice as a model system to understand how JunB normally controls HSC functions and to identify the deregulated mechanisms that are responsible for HSCs transformation into LSCs.