A central issue in normal and leukemic hematopoietic stem cell (HSC) biology is to understand the mechanisms that regulate self-renewal, which is required for hematopoiesis to persist for the lifetime of the animal. Stem cell self-renewal is under genetic constraints. Leukemia is a disease in which mutations allow either normal HSCs to escape the genetic constraints on self renewal or allow progenitor cells to acquire the ability to self-renew. To begin to understand the molecular mechanisms that regulate self-renewal, a cDNA library was constructed from pure populations of HSCs with self-renewal capacity and used to analyze genes that were differentially expressed by this population and pluripotent hematopoietic progenitor cells without self-renewal capacity. We found that the HSCs expressed the bmi1 oncogene, which is a Polycomb-group gene that represses expression of Hox genes during development and regulates cell proliferation and senescence by down-regulating the ink4a locus. The ink4a locus expresses two genes by alternative splicing: p16 is a G1 cyclin inhibitor and p19 ARF stabilizes expression of p53 by binding to Mdm2. We thus examined the HSC compartment in bmi1-deficient (""""""""knockout"""""""" or """"""""KO"""""""") mice and found that such mice had normal numbers of fetal liver HSCs. However, these mice displayed a reduction in adult HSCs and adult neuronal stem cells. Mutation of p16 Ink4a partially restores the stem cell defect in bmi-1 -/- mice. We then examined human HSCs and human AML stem cells and found that they both expressed bmi-1. This suggests that this gene may play a role in human hematopoiesis and leukemogenesis.
The aims of this grant are to extend these findings and to gain further insights into the regulation of stem cell functions, particularly self-renewal, via the following aims.
Specific Aim #1 : To determine whether alteration of the expression of putative bmi-1 downstream targets restores the ability of bmi-1 deficient bone marrow cells to give rise to leukemia.
Specific Aim #2 : To identify the target cell for transformation in AML induced by certain leukemia genes.
| Lobo, Neethan Amit; Zabala, Maider; Qian, Dalong et al. (2018) Serially transplantable mammary epithelial cells express the Thy-1 antigen. Breast Cancer Res 20:121 |
| Cai, Shang; Kalisky, Tomer; Sahoo, Debashis et al. (2017) A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland. Cell Stem Cell 20:247-260.e5 |
| Isobe, Taichi; Hisamori, Shigeo; Hogan, Daniel J et al. (2014) miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Elife 3: |
| Bockhorn, Jessica; Dalton, Rachel; Nwachukwu, Chika et al. (2013) MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nat Commun 4:1393 |
| Adorno, Maddalena; Sikandar, Shaheen; Mitra, Siddhartha S et al. (2013) Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature 501:380-4 |
| Rothenberg, Michael E; Nusse, Ysbrand; Kalisky, Tomer et al. (2012) Identification of a cKit(+) colonic crypt base secretory cell that supports Lgr5(+) stem cells in mice. Gastroenterology 142:1195-1205.e6 |
| Shimono, Yohei; Zabala, Maider; Cho, Robert W et al. (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138:592-603 |
| Diehn, Maximilian; Cho, Robert W; Lobo, Neethan A et al. (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780-3 |
| Lobo, Neethan A; Shimono, Yohei; Qian, Dalong et al. (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675-99 |
| Akala, Omobolaji O; Clarke, Michael F (2006) Hematopoietic stem cell self-renewal. Curr Opin Genet Dev 16:496-501 |
