Enhanced Self-Renewal of Hematopoietic Stem Cells Mediated by the Polycomb Gene Product Bmi-1

Abstract

The Polycomb group (PcG) gene Bmi-1 has recently been implicated in the maintenance of hematopoietic stem cells (HSC) from loss-of-function analysis. Here, we demonstrate that increased expression of Bmi-1 promotes HSC self-renewal. Forced expression of Bmi-1 enhanced symmetrical cell division of HSCs and mediated a higher probability of inheritance of stemness through cell division. Correspondingly, forced expression of Bmi-1, but not the other PcG genes, led to a striking ex vivo expansion of multipotential progenitors and marked augmentation of HSC repopulating capacity in vivo. Loss-of-function analyses revealed that among PcG genes, absence of Bmi-1 is preferentially linked with a profound defect in HSC self-renewal. Our findings define Bmi-1 as a central player in HSC self-renewal and demonstrate that Bmi-1 is a target for therapeutic manipulation of HSCs.

Epigenetic regulation of aging stem cells

“…Indeed, growing evidence suggests additional agerelated targets for BMI1 in addition to p16 INK4a /p19 ARF . Overexpression of Bmi1 in HSCs isolated from p19 ARF mutant mice and p16 INK4a /p19 ARF compound mutant mice can still enhance multipotency of HSCs in vitro (Iwama et al, 2004;Oguro et al, 2006). Furthermore, BMI1 plays a non-cell autonomous role in the bone marrow microenvironment that does not depend on p16 INK4a or p19 ARF (Oguro et al, 2006).…”

“…Loss of Bmi1 does not block the differentiation of more committed hematopoietic progenitors (Jacobs et al, 1999;Iwama et al, 2004), but affects the ability of stem and early progenitors to retain all cell fate choices. In culture, HSCs from young adult Bmi1-deficient mice have reduced multi-lineage potential compared with wild-type HSCs when assessed at early passage (Iwama et al, 2004). Bmi1's effects on HSC differentiation have been linked to its effects on chromatin state.…”

Hox genes in hematopoiesis and leukemogenesis

“…For example, the Polycomb group gene Bmi1 has emerged as a crucial regulator of HSC and LSC self-renewal (Lessard and Sauvageau, 2003;Park et al, 2003;Iwama et al, 2004). Bmi1 negatively regulates Hox gene expression during development (van der Lugt et al, 1996), thus it is surprising that its role in self-renewal has not been linked to Hox gene regulation.…”

Bmi1 Promotes Hepatic Stem Cell Expansion and Tumorigenicity in Both Ink4a/Arf -Dependent and -Independent Manners in Mice†

“…Bmi1 thus regulates HSCs by acting as a critical failsafe against the p16 Ink4a and p19 Arf -dependent senescence pathway. 10,11 Deletion of Ink4a/Arf similarly rescues neural stem cell (NSC) selfrenewal and frequencies in Bmi1-deficient mice, although its effect is reportedly partial. 12 In the oncogenic setting, the Ink4a-retinoblastoma protein (Rb) and Arf-p53 cellular senescence pathways trigger oncogene-induced senescence to eliminate transforming cells that potentially develop into cancer stem cells.…”