Angiogenin (ANG) is an angiogenic ribonuclease that has been shown by our lab to promote cancer cell proliferation by stimulating growth and survival pathways. We recently identified ANG as a novel regulator of hematopoietic stem cell (HSC) quiescence, suggesting that ANG differentially regulates cell growth in primitive versus mature cells. Quiescence is a vital property of stem cells, and is critical to maintaining normal stem cell behavior during crucial normal developmental processes, including hematopoiesis. Despite its protective role against stem cell exhaustion and malignancy, little is known about the factors that regulate HSC quiescence. We have demonstrated significantly elevated expression of ANG in primitive HSC populations and shown ANG control of stem cell pool size, cell cycle status, apoptotic activity, blood lineage differentiation, colony number, and mobilization. We also demonstrated stem cell exhaustion in a serial bone marrow (BM) transplantation model, indicating loss of quiescence in the absence of ANG. Moreover, several clinical studies have identified ANG as a factor upregulated in various hematological malignancies, including chronic myelogenous leukemia (CML), and aged Ang-/- mice develop a myeloproliferative disorder. This proposal aims to understand the exact functional role and mechanistic action of ANG during normal and malignant hematopoiesis. Based on our initial studies, we hypothesize that ANG controls stem cell quiescence in both a cell-autonomous and a non-cell autonomous manner during normal hematopoiesis, and the homeostatic control of ANG is disrupted in the malignant state. In this study we will (1) establish the requirement of ANG for HSC activity in vitro and in vivo, (2) determine the mechanism by which ANG maintains HSC quiescence, and (3) investigate the role of ANG and its receptor in leukemogenesis. Given that ANG has been shown to regulate quiescence, at least in part, in a non-cell autonomous manner in BM, we propose to identify the physiologically-relevant cell-of-origin of ANG in the BM niche using conditional knockout models developed by our lab. We will also identify the receptor through which ANG promotes HSC quiescence non-cell autonomously, and demonstrate therapeutic potential of this axis in vitro and in vivo. Moreover, we will identify ANG as a novel regulator of ribosomal activity and protein synthesis in HSCs and leukemia, and identify novel downstream targets in regulating quiescence. Last, we will examine its function and mechanism using a BCR-ABL model of leukemogenesis. Our study will identify ANG as a novel factor that is simultaneously a conductor of the quiescent state in normal HSCs and a potent regulator of the leukemic state. Since the homeostatic balance of critical stem cell properties is necessary for maintained blood production and prevention of malignant transformation, the understanding of factors that uniquely regulate this balance, such as ANG, is necessary for the development of key therapeutics in a variety of BM disorders, hematological malignancies, and in regenerative medicine.
The long-term goal of this project is to functionally characterize ANG as a novel regulator of key stem cell properties in the bone marrow microenvironment. While these proposed studies will identify ANG as a significant therapeutic target in stem cell transplantation, bone marrow disorders and hematological malignancies, these studies will also serve as a model for other cancers, as ANG may act in the bone marrow microenvironment to harbor metastatic cells, diminishing the effectiveness of currently-utilized therapies.
| Yu, Wenhao; Goncalves, Kevin A; Li, Shuping et al. (2017) Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin. Cell 171:849-864.e25 |
| Silberstein, Lev; Goncalves, Kevin A; Kharchenko, Peter V et al. (2016) Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators. Cell Stem Cell 19:530-543 |
| Goncalves, Kevin A; Silberstein, Lev; Li, Shuping et al. (2016) Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells. Cell 166:894-906 |
| Goncalves, Kevin A; Hu, Guo-Fu (2015) Mechanism and Function of Angiogenin in Hematopoietic Malignancy. Zhongguo sheng wu hua xue yu fen zi sheng wu xue bao = Chinese 31:1267-1275 |
