The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steadystate hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reac- IntroductionThe transcription factor Meis1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins, which also includes Pbx1. Meis1 was originally discovered as a target of activation by retroviral integration in the leukemic mouse strain BXH-2. In these mice, Meis1 was always found coactivated with Hoxa7 or Hoxa9. 1 Experimental overexpression of Meis1 and Hoxa9 in hematopoietic cells leads to an aggressive leukemia in mice. 2 In normal hematopoiesis, Meis1 expression among the various cell compartments is correlated with the degree of selfrenewal, with the levels being highest in hematopoietic stem cells (HSCs) and declining with differentiation. 3,4 These results, combined with those from studies in leukemia, suggest a role for Meis1 in HSC self-renewal. However, the functions of Meis1 in established hematopoiesis remain unknown. Meis1 Ϫ/Ϫ mice die by embryonic day 14.5 and the embryos display extensive hemorrhaging, particularly in the CNS. In addition, fetal liver cells obtained from Meis1 Ϫ/Ϫ embryos show reduced myeloid colony formation in vitro and perform poorly in competitive transplantation assays in vivo. 5,6 These results show that Meis1 is critical in the development of hematopoiesis. Further, Meis1 Ϫ/Ϫ embryos display defects in capillary formation, suggesting additional roles for Meis1 in mechanisms that regulate the process of angiogenesis, at least during development.Previous studies showed that Meis1 and Pbx1 can form heterodimeric and heterotrimeric complexes with HOX proteins, augmenting the binding and activation of target genes by HOX proteins such as HOXA9. 7,8 Deletion of Pbx1 in the hematopoietic system led to loss of quiescence in HSCs, resulting in hematopoietic failure. 9 Given that both Pbx1 and Meis1 are expressed in HSCs, we hypothesized that Meis1 might also be required for the maintenance of the self-renewing HSCs. In the present study, we investigated the role of Meis1 in established hematopoiesis using inducible knock-out mice. We found that Meis1 is required for the maintenance of HSCs by preserving quiescence in these mice. Maintenance of quiescence is critical for preserving self-renewal of long-term stem cells, and various signaling pathways have been shown to modulate quiescence in HSC...
Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators of LSD1, has previously been described. Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all- trans retinoic acid was explored. All- trans retinoic acid is currently approved for use in acute promyelocytic leukemia in which it promotes differentiation of abnormal blast cells into normal white blood cells. Combined treatment with all- trans retinoic acid and GSK2879552 results in synergistic effects on cell proliferation, markers of differentiation, and, most importantly, cytotoxicity. Ultimately the combination potential for LSD1 inhibition and ATRA will require validation in acute myeloid leukemia patients, and clinical studies to assess this are currently underway.
The mammary gland is a dynamic organ that only undergoes complete differentiation during pregnancy. Differentiation is fuelled by asymmetric division of stem cells that reside in normally quiescent niches in the resting gland in response to pregnancy-associated hormones. Loss of regulation of stem cells is believed to underlie some breast cancers. This process is poorly understood in humans since it is difficult to extract stem cells from the lactating gland. We have identified a p63-positive population in breastmilk that proliferates and differentiates into at least two separate mammary lineages in culture. Nuclear translocation of p63 coincides with expression of the cell-cycle arrest protein 14-3-3σ (Sigma) and precedes differentiation. Transient down-regulation of Sigma promotes maintenance of the p63-positive population without affecting normal differentiation. We propose that p63-postive cells from breastmilk represent a novel source of cells to model regulation of mammary gland development and tumorigenesis.
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