As a pediatric hematologist/oncologist/stem cell transplant physician, my work has focused on discovering and developing novel therapies for hematopoietic disorders. In particular, I have used mass spectrometry to identify the non-genetic determinants underlying functional differences in stem and progenitor cell state. At City of Hope, we will continue to develop and use small-scale proteomic technologies to identify key components responsible for benign and malignant hematopoietic stem cell survival and maintenance, collaborating to develop effective therapeutic agents for improving mobilization and engraftment of donor hematopoietic cells, and devising effective patient-specific therapies to eradicate leukemia stem cells. Additionally, we will use small-scale proteomic technologies to advance the immunotherapy of malignant disease. Chimeric antigen receptor (CAR) therapies have found limited application in solid tumors, in part due to the paucity of attractive CAR target antigens on solid tumors. Finally, we will continue to collaborate on genome editing projects in hematopoietic stem and progenitor cells.
Proteomics of ARHGAP25. In collaboration with Jarrod Marto’s group at the Dana-Farber Cancer Institute, I have developed a novel discovery platform that enables comprehensive investigations into the proteomic landscape of rare primary hematopoietic cell populations at a previously impossible resolution (below). We used this powerful new tool to compare resting and mobilized HSPCs, and identified a list of high-priority candidates likely to be important in HSPC mobilization and engraftment. This work, which was published in Blood, identified the novel Rac-GAP ARHGAP25 as an important mediator of HSPC mobilization, development, and malignancy, providing a potential stem-cell specific therapeutic target (right).
Work in our lab will continue to study the mechanisms through which ARHGAP25 phosphorylation affects its function in hematopoiesis and leukemogenesis, using a variety of studies in animals and with human samples.
Proteomic interrogation of human leukemia stem cells. In collaboration with Dr. Sonja Hess at Caltech and Dr. Markus Kalkum at City of Hope, we are improving on our published technology to achieve better resolution in less instrument time and with better compensation for TMT interference. We will use our improved platform to define the phosphoproteomic features of adult and pediatric leukemia stem cells (below). This will make possible the proteomic profiling of individual patient samples, permitting the generation of unique patient-specific phosphoproteomic fingerprints and realizing the potential of precision medicine on a proteomic level.
Mass spectrometry-based profiling of tumor-responsive immune cells. City of Hope is a world leader in immuno-oncology, and at the forefront of the chimeric antigen receptor (CAR) T cell revolution. Although this powerful new therapy has had some remarkable successes, its use in solid tumors is limited by several factors, including a failure of CAR T cells to persist in situ. In collaboration with Dr. Christine Brown, our lab is working to identify a proteomic signature of CAR T cell persistence in xenotransplantation models of pediatric brain tumors. This will permit improved engineering of these cells for solid tumor immunotherapy.
Gene therapy for hematologic disorders. During my postdoctoral fellowship, I worked on translational gene therapy with David Williams and served as the co-PI of a Phase I/II clinical trial of a novel lentiviral vector for the gene correction of X-CGD (overall PI: Don Kohn, UCLA). I was also a part of an NIH Nanomedicine Center for Nucleoprotein Machines, which aimed to develop strategies for TALEN-mediated gene correction of sickle cell beta-globin. I plan to continue this work at City of Hope in collaboration with Dr. Saswati Chatterjee, whose groundbreaking work on AAV-based vectors is reshaping how we think about gene therapy.
Stay up to date on all our research!
Wang LD, Ficarro SB, Hutchinson JN, Csepanyi-Komi R, Nguyen PT, Wisniewski E, Sullivan J, Hofmann O, Ligeti E, Marto JA, Wagers AJ.
Blood. 2016; 128(11):1465-74.
Rowe RG, Wang LD, Coma S, Han A, Mathieu R, Pearson DS, Ross S, Sousa P, Nguyen PT, Rodriguez A, Wagers AJ, Daley GQ.
The Journal of experimental medicine. 2016; 213(8):1497-512.
Wang LD, Rao TN, Rowe RG, Nguyen PT, Sullivan JL, Pearson DS, Doulatov S, Wu L, Lindsley RC, Zhu H, DeAngelo DJ, Daley GQ, Wagers AJ.
Leukemia. 2015; 29(6):1320-30. NIHMSID: NIHMS662665
- Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow.
Nabors LK, Wang LD, Wagers AJ, Kansas GS.
Experimental hematology. 2013; 41(7):588-96. NIHMSID: NIHMS475023
Wang LD, Wagers AJ.
Nature reviews. Molecular cell biology. 2011; 12(10):643-55. NIHMSID: NIHMS571834