During the last year, we continued to define the molecular events that regulate hematopoietic stem and progenitor cell (HSPC) quiescence, survival, self-renewal and, myeloid cell lineage commitment and differentiation. We have focused our efforts on transcription factors since they are essential for stem cell growth and differentiation and are frequently deregulated during the development of leukemias and lymphomas. We previously found that the helix loop helix (HLH) transcription factor, inhibitor of differentiation 1 (Id1), is induced during the early stages of myeloid development, and can instruct hematopoietic stem cells toward a myeloid versus erythroid and lymphoid cell fate suggesting that this gene and other family members Id2 and Id3 may regulate cell specification of HSPC. We also discovered that Id genes are required for the proper function of the hematopoietic microenvironment (HME). Specifically, we found that loss of Id1 and Id3 in the HME resulted in increased RBCs present in the bone marrow extravascular space, suggesting that Id genes might be required for proper endothelial cell (EC) function. We confirmed that Id genes are required for the proper function of endothelial cells using a mouse model that specifically deletes Id1/Id3 in endothelial cells. Specifically, we determined that loss of Id1 and Id3 in adult endothelial cells results in a severe disruption of vascular integrity in the bone marrow that results in dilated and hemorrhagic sinusoid ECs (SECs), which increases in severity over time. In addition, we found that these mice that these mice show increased HSC activation and reduced HSC quiescence that leads to loss of HSC numbers and function. Mechanistically, we found that adult ECs that lack Id1 and Id3 show decreased proliferative potential by increased expression of cyclin dependent kinases, and increased apoptosis by reduced Bcl-xl expression. In other studies, we discovered that mice that lacked Id1 show enhanced HSC self-renewal in serial bone marrow transplant assays. We found that the Id1-/- HSCs show reduced cell cycling and reduced levels of H2AX staining suggesting that the Id1-/- HSC show increased quiescence during BMT. We also found that the Id1-/- HSCs show reduced mitochondrial biogenesis, reduced ROS production and increased levels of reduced glutathione confirming that Id1-/- HSCs show increased quiescence after BMT. Further studies suggest that loss of Id1 leads to increased E protein activity and increased expression of cyclin dependent kinase inhibitors, which promotes HSC quiescence. Collectively, we provide evidence that Id1-/- HSCs are protected from proliferative exhaustion during BMT, chronic stress and aging. These studies laid the foundation for our current studies to determine if Id genes promote clonal hematopoiesis, and if reducing Id1 expression can reduce hematopoietic stem and progenitor (HSPC) cell cycling and clonal expansion and reduce the incidence of hematopoietic malignancies. Specifically, we found that Id gene expression is increased HSPC progenitor cells from Tet2-/- mice, a murine model of clonal hematopoiesis. Subsequently we have determined that reducing Id1 levels in Tet2-/- mice rescues the HSPC hyperproliferation in vitro, and in bone marrow transplantation assays in vivo, which suggest that we can reduce clonal hematopoiesis in this model. Future studies are aimed at demonstrating that reducing Id1 gene expression reduces the mutational load in HSPCs in vivo, and the frequency of hematopoietic malignancies in this model. We are also pursing studies to determine if reducing Id1 levels in the Fanconi anemia model, Fancd2, can rescue HSC exhaustion and reduce the incidence of hematopoietic malignancies.

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National Cancer Institute (NCI)
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Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly et al. (2017) RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice. PLoS One 12:e0171510
Nickerson, M L; Das, S; Im, K M et al. (2017) TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene 36:2172-2183
Qu, Peng; Wang, Lizhen; Min, Yongfen et al. (2016) Vav1 Regulates Mesenchymal Stem Cell Differentiation Decision Between Adipocyte and Chondrocyte via Sirt1. Stem Cells 34:1934-46
Baba, Masaya; Toyama, Hirofumi; Sun, Lei et al. (2016) Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure. Stem Cells 34:1068-82
Puverel, Sandrine; Kiris, Erkan; Singh, Satyendra et al. (2016) RanBPM (RanBP9) regulates mouse c-Kit receptor level and is essential for normal development of bone marrow progenitor cells. Oncotarget 7:85109-85123
Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M et al. (2016) Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J 30:262-75
Kim, Wonil; Klarmann, Kimberly D; Keller, Jonathan R (2014) Gfi-1 regulates the erythroid transcription factor network through Id2 repression in murine hematopoietic progenitor cells. Blood 124:1586-96
Satyanarayana, Ande; Klarmann, Kimberly D; Gavrilova, Oksana et al. (2012) Ablation of the transcriptional regulator Id1 enhances energy expenditure, increases insulin sensitivity, and protects against age and diet induced insulin resistance, and hepatosteatosis. FASEB J 26:309-23
Gudmundsson, Kristbjorn Orri; Stull, Steven W; Keller, Jonathan R (2012) Transplantation of mouse fetal liver cells for analyzing the function of hematopoietic stem and progenitor cells. Methods Mol Biol 879:123-33
Oakley, Kevin; Han, Yufen; Vishwakarma, Bandana A et al. (2012) Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10. Blood 119:6099-108

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