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Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USAAlbert Einstein Cancer Center and Einstein Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
show that loss-of-function mutations in RUNX1 reduce ribosome biogenesis and provide pre-LSCs a selective advantage over normal hematopoietic cells through increased stress resistance.
The myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal bone marrow malignancies characterized by ineffective hematopoiesis, the presence of dysplastic cells in the bone marrow, and peripheral blood cytopenias. MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy (
). Transformational genetic and epigenetic changes are believed to selectively expand pre-LSCs in the bone marrow, which then out-compete normal hematopoietic stem and progenitor cells (HSPCs). Genome-wide studies have recently identified a number of genetic lesions that are implicated in this process and the development and/or progression of MDS. These lesions have so far been found in splicing factor genes (e.g., SF3B1 and SRSF2) as well as genes involved in regulating DNA methylation (e.g., TET2, IDH, and DNMT3A), histone modification (e.g., ASXL1 and EZH2), and several signal transduction and transcription factors (e.g., RUNX1, p53, EVI1, JAK2, and FLT3). In this issue of Cell Stem Cell,
show that mutations in the transcription factor RUNX1 reduce ribosomal biogenesis and provide a competitive advantage to pre-LSCs by enhancing stress resistance.
Almost half of MDS patients present with recurring karyotypic abnormalities affecting chromosomes 5, 7, 8, and 20, many of which impact the ribosome. Hemizygous loss of the ribosomal protein gene Rps14 contributes to the development of anemia in 5q− syndrome (
). Other genetic abnormalities cause impaired ribosome biogenesis (Ribi) and function—a collection of disorders known as ribosomopathies. Researchers have also found an association between ribosomal stress and activation of p53. In their current study, Cai et al. have focused on Runx1, a DNA binding transcription factor that is found mutated in MDS and AML, particularly in patients with previous exposure to genotoxic agents. In the mouse, loss-of-function mutations of Runx1 cause defects in lymphocyte and megakaryocytic development (
). Early events such as RUNX1 mutations are known to generate pre-LSCs. However, the molecular mechanisms underlying the competitive expansion of pre-LSCs through loss-of-function RUNX1 mutation have yet to be fully understood.
Cai and colleagues now elucidate some of the precise machinery involved in this process. Using conditional Runx1-deficient mice, they first found that Runx1 deficiency protects HSPCs from various stresses. Runx1-ablated HSPCs expanded in the bone marrow relative to competitor cells, when donor cells were subjected to a low level of irradiation prior to transplantation. Less apoptosis was observed in Runx1Δ/Δ HSPCs after Ara-C treatment and endoplasmic reticulum (ER) stress induced by tunicamycin. Based on these data, Cai et al. concluded that Runx1-deficient HSPCs are resistant to both genotoxic and endogenous stresses. Runx1-deficient HSPCs are slow cycling and have a low metabolic profile, small cell phenotype, and decreased biosynthetic capacity with a balanced reduction in Ribi. To understand the mechanisms underlying decreased Ribi, they analyzed ChIP-seq data generated in human CD34+ HSPCs and found that RUNX1 binding is highly enriched at the promoters of Ribi genes. In murine Runx1Δ/Δ HSPCs, expression levels of ribosome genes occupied by RUNX1 were reduced. Acute deletion of Runx1 in vitro decreases 45S rRNA and the translational rate in HSPCs. These data suggest that RUNX1 directly regulates Ribi through its enriched binding at the promoters of Ribi genes, including the genes encoding structural components of the ribosome. Interestingly, Runx1-deficient HSPCs have lower levels of p53 protein and reduced apoptosis. Increased levels of p53 or its target genes by radiation were also attenuated in Runx1Δ/Δ HSPCs. Activation of p53 alone fails to reverse the low apoptotic phenotype in Runx1-deleted HSPCs, and increased mTOR signaling partially restores Ribi, but not their reduced apoptotic phenotype.
While these findings represent a step forward in developing a coherent picture of the competition between pre-LSCs and HSPCs and how this may lead to full-blown malignancies, many gaps remain in this developing story. Perhaps Cai et al.’s most compelling new findings are the links demonstrated between Runx1 mutations, reduced Ribi, and p53-independent stress resistance phenotypes. These findings, however, raise a series of theoretical issues. One such question is the mechanism of how the changes in Ribi induced by Runx1 mutations lead to stress resistance in HSPCs. In other words, is this phenomenon simply the result of slow growth resulting from Runx1 deficiency, or do other mechanisms contribute specifically in the case of reduced Ribi? It will also be interesting to explore which ribosome genes are major players in Ribi phenotypes induced by Runx1 mutations.
For example, are one or a few members of the perturbed ribosome genes able to restore the phenotype of Runx1-mutated HSPCs? Located on chromosomal 21, the RUNX1 gene is also involved in chromosomal translocations in leukemia, and the RUNX1-ETO fusion protein by t(8;21) is one of the most common translocations in AML (
). It will also be interesting to unravel whether Ribi contributes to leukemia pathogenesis induced by RUNX1 fusion proteins. The answer to these questions will no doubt be the focus of future studies, which will lead to a deeper characterization of these mechanisms, such as specific downstream targets, and the development of new therapeutic approaches designed to eradicate stress-resistant leukemic and pre-leukemic HSPCs while restoring normal hematopoiesis (Figure 1). As ribosomopathies have also been associated with an increased predisposition to cancer, these findings may have wide-ranging implications in other cancers.
Loss-of-function RUNX1 mutations are common in myelodysplastic syndrome and leukemia and can be early events. Cai et al. demonstrate that Runx1 loss decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells and confers resistance to endogenous and genotoxic stress.