The long-term objective of this project is to obtain a better understanding of the control mechanisms involved in regulating the processes of self-renewal, proliferation, and differentiation in normal and malignant hematopoietic stem-progenitor cells. This understanding is necessary in order to rationally manipulate these cells for optimal use in transplantation and to develop new methods for treating transformed cells. Our premise is that the study for STK-1 (FLT3/FLK-2) is likely to further our understanding of both normal and abnormal hematopoiesis. We were the first to clone and study the human receptor. We found it to be restricted in expression to the CD34+ fraction of human bone marrow though more recently we have also found it to be expressed on CD34- monocytic precursors (CD15+). We showed that antisense inhibition of STK-1 expression by CD34+ cells in the long-term bone marrow culture assays (which is reflective of stem-progenitor cell activity) suppressed hematopoietic colony formation. We then showed that STK-1 was over- expressed at both the RNA and protein level by leukemia cells in patients with B-lineage ALL (100%), AML (90%), and subsets of CML (blast crisis- 30%), T-ALL (30%), and CLL (67%). FL, the ligand for this receptor has undergone a profusion of studies over the last 2 years. The ligand shows promise for potential clinical use to increase the mobilization of stem- progenitor cells for harvest, to expand stem/progenitor cells, and to facilitate retroviral transduction of stem/progenitor cells for gene therapy. Our proposal is a natural extension of our ongoing work on STK-1. Although its ligand is being intensively studied, little is known of the regulation of the receptor. In addition, the receptor is aberrantly expressed in leukemia and nothing is known of the reasons for this alteration. Thus, our work will concentrate on the mechanism(s) for both the normal and abnormal control of receptor expression. We propose an initial scrutiny of the approximately 900 bp upstream of the transcription start site. We will delineate both cis elements and trans acting factors important for STK-1's expression and regulation. We also propose to investigate the role that STK-1 expression may play in leukemia. We will determine if it gives leukemic cells a survival and/or proliferative advantage. We will also model the effects of an activated receptor by generating a fusion protein that results in constitutive activation of the tyrosine kinase domain.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Gamper, Christopher J; Takemoto, Clifford M; Chen, Allen R et al. (2016) High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia. J Pediatr Hematol Oncol 38:627-635
Fox, Jennifer M; Moynihan, James R; Mott, Bryan T et al. (2016) Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget 7:7268-79
Sharrow, Allison C; Perkins, Brandy; Collector, Michael I et al. (2016) Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy. Gynecol Oncol 142:341-8
Kim, MinJung; Tan, Yee Sun; Cheng, Wen-Chih et al. (2015) MIR144 and MIR451 regulate human erythropoiesis via RAB14. Br J Haematol 168:583-97
Candia, Julián; Cherukuri, Srujana; Guo, Yin et al. (2015) Uncovering low-dimensional, miR-based signatures of acute myeloid and lymphoblastic leukemias with a machine-learning-driven network approach. Converg Sci Phys Oncol 1:
Brodsky, Robert A (2014) Paroxysmal nocturnal hemoglobinuria. Blood 124:2804-11
Rau, Rachel; Magoon, Daniel; Greenblatt, Sarah et al. (2014) NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. Exp Hematol 42:101-13.e5
Tan, Yee Sun; Kim, MinJung; Kingsbury, Tami J et al. (2014) Regulation of RAB5C is important for the growth inhibitory effects of MiR-509 in human precursor-B acute lymphoblastic leukemia. PLoS One 9:e111777
Ma, Hayley S; Nguyen, Bao; Duffield, Amy S et al. (2014) FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia. Cancer Res 74:5206-17
Belet, Stefanie; Fieremans, Nathalie; Yuan, Xuan et al. (2014) Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality. Hum Mutat 35:350-5

Showing the most recent 10 out of 60 publications