RUNX genes find a niche in stem cell biology

Abstract

The RUNX family of transcriptional regulators are well conserved throughout the animal kingdom, from the simple nematode worm Caenorhabditis elegans to vertebrates. Interest in the RUNX genes emerged principally as a result of the finding that chromosomal translocations disrupting RUNX protein function are observed in a large number of patients suffering with acute myeloid leukemia (AML). In the 20 years that RUNX genes have been under investigation, they have emerged as central players in the control of developmental decisions between proliferation and differentiation in a wide variety of biological situations. This review focuses on recent data highlighting the roles of RUNX genes in stem cells and illustrates the diversity of processes in which the RUNX proteins play a critical role. In particular, we focus on the role of RUNX1 in hematopoietic stem cells (HSCs) and hair follicle stem cells (HFSCs) and the importance of the solo C. elegans RUNX factor rnt-1 in stem cell proliferation in the worm. Observations in a variety of stem cell systems have developed to the point where useful comparisons can be made, from which guiding principles may emerge. J. Cell. Biochem. 108: 14-21, 2009. ß 2009 Wiley-Liss, Inc. KEY WORDS: RUNX; STEM CELLS; HEMATOPOIESIS; HAIR FOLLICLE; C. ELEGANSA central and recurrent theme in the development of multicellular organisms is the establishment of disparate cell and tissue types from a single fertilized zygote. Somatic stem cells provide the means by which from a limited pool of undifferentiated cells, multipotent daughters can arise, destined for a variety of tissue types. Stem cells are able to divide asymmetrically (self-renewal maintenance) to maintain overall stem cell number and provide more specialized progenitors, which may then embark on one or more specific developmental programmes before becoming terminally differentiated. Alternatively, stem cells may undergo symmetric (self-renewal expansion) division, to repopulate the stem cell niche. In tissue homeostasis, stem cells are pivotal since they are essential for supplying replacements for short-lived cells, as in the case of hematopoiesis, or in tissue repair. Stem cell developmental programmes therefore need to be tightly regulated; if developmental programmes of progenitors are not properly controlled they may fail to mature, or follow inappropriate paths to differentiation; if the homeostasis of the stem cell itself is disrupted, too few progenitors may be available. It is therefore apparent that at the heart of proper stem cell function are the mechanisms that regulate the developmental decision between cell division and differentiation.The RUNX family of transcription factors have recently emerged as major players in the control of stem cell differentiation and proliferation in both cancer and developmental biology. With the advent of genome sequencing, RUNX genes have now been identified in a wide range of animal species, from worms to fish, sea urchins to mice. In mouse, Runx1 has recently been identified as ...

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

“…To check if the Runx1 cKO skin responded differently at the molecular level to TPA treatment, we checked for expression of several selected markers previously reported to be regulated during tumorigenesis (2,60). The differentiation markers keratin 1, 5, and 15 and ␣6-integrin, Loricrin, and E-cadherin were expressed in both WT and cKO skin and revealed consistently lower stratification and expansion of the epidermis and the infundibulum in cKO skin (Fig.…”

“…Runx1 is part of the small Runt domain family of transcription factors implicated in tissue stem cell regulation (2), tissue development (14), and cancer (8). Runx1 plays developmental roles in several organs, including blood (54), muscle (65), the nervous system (26,69), and hair follicles (HFs) (44,47), by affecting cell survival, proliferation, and differentiation (14).…”

“…Runx1 is required in mouse embryos for adult hematopoietic stem cell (HSC) emergence (11,54), while in adult mice it affects specific hematopoietic lineages (21,25,46,56). The role of Runx1 in epithelial skin and HFs, an important model system for stem cell regulation and cancer progression, has just begun to be addressed (2).…”

Regulation of Postnatal Forebrain Amoeboid Microglial Cell Proliferation and Development by the Transcription Factor Runx1

“…Runx1 regulates cell proliferation in a variety of contexts (Theriault et al, 2005;Hoi et al, 2010;Link et al, 2010). Moreover, Runx1, as well as other Runx proteins, can coordinate cell cycle exit with the progression to a more developmentally mature state in a number of cell lineages (Kagoshima et al, 2007;Appleford and Woollard, 2009). Together, these observations strongly suggest that at least one role of Runx1 in the postnatal forebrain is to inhibit the proliferative capacity of amoeboid microglia.…”

CBFB–MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia

“…1 They are heterodimeric complexes consisting of two subunits, alpha and beta, in which the alpha subunit binds to DNA and is encoded by one of the RUNX1 (AML1, CBFa2), RUNX2 (CBFa1) and RUNX3 (CBFa3) genes, whereas the beta subunit (CBFb) is thought not to bind to DNA but to stabilize the DNA binding of the alpha subunit. RUNX1 is the CBF alpha subunit that is predominantly expressed during hematopoietic development, and both RUNX1 and CBFb are frequently involved in chromosomal alterations associated with hematopoietic diseases, for example, in t(8;21) and inv (16) acute myeloid leukemia (AMLs).…”