Xiaomiao Li, PhD
Research Assistant Professor
2011 Mowry Road
Cancer and Genetics Research Complex, Room 475E
Gainesville, FL. 32611
My work is focused on the following major projects:
1. Screening small molecules against CRLF2
The type I cytokine receptor subunit CRLF-2 is emerging as an important receptor that is either upregulated or mutated in patients with the highest risk forms of pediatric acute lymphoblastic leukemia. Upregulation of CRLF-2 is also associated with mutations of Jak-2. We are searching for small molecule inhibitors to CRLF-2 by testing selected compounds through a molecular docking method. We have tested the activity of these inhibitors on Ba/F3 cells transformed by retrovirus carrying a human CRLF-2 activating mutation Phe232Cys. This mutation converts the Ba/F3 cells, which are normally IL-3 dependent, to have IL3-independent growth. Compounds that inhibit CRLF-2 function will inhibit this IL-3-independent growth. On the first screening of 40 compounds, two of them have been identified that inhibit transformed Ba/F3 cell growth. The IC50s are 0.2756uM and 7.4uM respectively. These inhibitors will be further tested in a NOD-SCID mouse model that harbors the mutated CRLF-2 to test its effect on inhibiting leukemia development. So far, we have injected the Ba/F3 cells harboring the CRLF-2 mutation into NOD-SCID mice too see if the mice will develop leukemia. Also 10 primary samples from pediatric preB-ALL patients have been tested for CRLF-2 expression and one of them shown 70% of cell express CRLF-2. The cells from this sample have been injected into NOD-SCID subjects to generate a model for testing the effectiveness of the small molecules on the treatment of this type of leukemia in subjects.
2. Studying the interaction of hematopoietic stem, progenitor cells with bone marrow sinusoids during engraftment in order to improve the outcome of platelet production after bone marrow transplant.
It has been shown that after myelosuppression agent 5-Fu treatment, the re-bounce of the platelet count can reach up to 200% of the steady-state platelet count. We did not see this level of platelet re-bounce in sub-lethal radiation treated mice. Application of a Tie-2 inhibitor Tie-2/Fc can inhibit this re-bounce. The current explanation of this suppression is that the sinusoidal endothelial cells undergo complete degeneration after the treatment, and Tie-2, as an angiogenesis factor is required for the neovacuolization of the sinusoids to support the megakaryocyte maturation. From our study of the sinusoidal recovery after 5-Fu treatment, we found no evidence for a vast degeneration of the sinusoidal system and no evidence for neovacuolization. Instead, the majority of the sinusoidal endothelial cells survived the treatment. Therefore, the argument of Tie-2 inhibitor inhibits sinusoids regeneration as the reason for inhibiting the platelet count re-bounce is not supported. Besides expressed in the endothelial cells, Tie-2 is also expressed in hematopoietic stem cells. The focus of this study is to investigate how the Tie-2 inhibitor inhibits the interaction of the hematopoietic stem cells and its microenvironment, and how this intereation leads to the re-bounce platelet after 5-Fu treatment. We are hoping that the information we get from this research will help to enhance platelet production after bone marrow transplantation.
Dr. Li received her PH.D. Degree from City University of New York in 1987. She received the postdoctoral training in Medical Genetics in Harbor UCLA medical Center and moved to San Francisco and worked at UCSF in 1991. In 2003, she joined the Bill Slayton’s lab in the University of Florida.
Additional publications can be found in PubMed.
- Li XM, Hu Z, Zafar AB, Jorgensen ML, Bungert J, Slayton WB. Intrinsic and extrinsic effects of mafG deficiency on hematopoietic recovery following bone marrow transplant. Exp Hematol. Dec;38(12):1251-60, 2010
- Li XM, Hu Z, Jorgenson ML, Slayton WB. High Levels of Acetylated Low-Density Lipoprotein Uptake and Low Tyrosine Kinase With Immunoglobulin and Epidermal Growth Factor Homology Domains-2 (Tie2) Promoter Activity Distinguish Sinusoids From Other Vessel Types in Murine Bone Marrow. Circulation. Nov 10;120(19): 1910-8, 2009
- Li XM, Hu Z, Jorgenson ML, Wingard JR, Slayton WB. Bone marrow sinusoidal endothelial cells undergo nonapoptotic cell death and are replaced by proliferating sinusoidal cells in situ to maintain the vascular niche following lethal irradiation. Exp. Hematol. 36(9) 1143-1156, 2008
- Slayton WB., Li X-M., Butler J., Guthrie SM., Jorgensen ML., Wingard JR., Scott EW. The role of the donor in the repair of the marrow vascular niche following hematopoietic stem cell transplant. Stem Cells 25(11) 2945-2955, 2007.
- Li X-M, Hu Z., Sola-Visner M., Hensel S., Garner R., Zafar AB., Wingard JR., Jorgensen ML., Fisher RC., Scott EW., Slayton WB. Sites and kinetics of donor thrombopoiesis following transplantation of whole bone marrow and progenitor subsets. Exp Hematol. 35 (10), 1567-1579, 2007