Runx1Protects Hematopoietic Stem/Progenitor Cells from Oncogenic Insult

Abstract

The RUNX1/AML1 gene encodes a transcription factor essential for the generation of hematopoietic stem cells and is frequently targeted in human leukemia. In human RUNX1-related leukemias, the RAS pathway is often concurrently mutated, but the mechanism of the synergism remains elusive. Here, we found that inactivation of Runx1 in mouse bone marrow cells results in an increase in the stem/progenitor cell fraction due to suppression of apoptosis and elevated expression of the polycomb gene Bmi-1, which is important for stem cell self-renewal. Introduction of oncogenic N-RAS into wild-type cells, in contrast, reduced the stem/ progenitor cell fraction because of senescence, apoptosis, and differentiation. Such detrimental events presumably occurred because of the cellular fail-safe program, although hyperproliferation was initially induced by an oncogenic stimulus. Runx1 insufficiency appears to impair such a failsafe mechanism, particularly in the stem/progenitor cells, thereby supporting the clonal maintenance of leukemiainitiating cells expressing an activated oncogene. STEM CELLS

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

“…P-values represent the average of at least five samples, P: ns (P40.05), *Po0.05, ***Po0.001, one-way analysis of variance maintenance, and cancer progression. [18][19][20] Moreover, we observed significant epigenetic changes of the methylation status on the promoter region of four genes associated with stemness and self-renewal (FOS, 21 Olig2, 22 RUNX1, 23 and SMAD2 24 ) in DN GBM cells treated with TMZ (Supplementary Figure S4B). These results provide new clues regarding the mechanisms of TMZ-mediated GSC amplification and require further investigation.…”

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…Triggered by oncogenes such as RAS through reactive oxygen speciesinduced DNA damage and DNA hyperreplication (Di Micco et al, 2006), oncogene-induced senescence is an important mode of tumor suppression, which blocks aberrant proliferative signals. Mounting evidence have suggested cooperation between RUNX proteins and RAS pathways during tumorigenesis: concurrent mutations in RUNX1 and RAS pathways are extremely frequent in RUNX1-related leukemia cases; Runx1 deficiency suppresses N-RAS-induced senescence and apoptosis, most likely through upregulation of Bmi-1 and Bcl-2 and consequent suppression of p16 Ink4a and p19 Arf expression (Motoda et al, 2007); RUNX3, similar to other RUNX family members, functions as a mediator of oncogene-induced senescence: it induces a p14 ARF -p53-dependent growth arrest in primary mouse embryonic fibroblasts that is reminiscent of senescence (Kilbey et al, 2007. Future studies may reveal the degree to which RUNX family members are biologically linked to senescence.…”

Runx3 deficiency results in myeloproliferative disorder in aged mice

“…RUNX1 is abrogated by multiple types of genetic alterations in human hematological malignancies [3][4][5] and is critical for the generation and maintenance of hematopoietic stem cells (HSCs). [6][7][8][9][10] Runx1 regulates the expression of stemnessand niche-related factors, such as Bmi1, Cxcr4, and integrin a 2 , deregulation of which in adult Runx1 knockout (KO) mice led to an expanded hematopoietic stem/progenitor cell (HSPC) compartment and subsequent stem cell exhaustion. [6][7][8][9][10][11][12] In addition, adult Runx1 KO mice show abnormal megakaryocytic differentiation and defective lymphoid development.…”

“…[6][7][8][9][10] Runx1 regulates the expression of stemnessand niche-related factors, such as Bmi1, Cxcr4, and integrin a 2 , deregulation of which in adult Runx1 knockout (KO) mice led to an expanded hematopoietic stem/progenitor cell (HSPC) compartment and subsequent stem cell exhaustion. [6][7][8][9][10][11][12] In addition, adult Runx1 KO mice show abnormal megakaryocytic differentiation and defective lymphoid development. [11][12][13][14] In contrast, the role of Runx3 in hematopoiesis remains elusive, despite the fact that Runx3 is expressed in various hematopoietic tissues in adult mice.…”