Jeff Bailey
Cincinnati Children's Hospital Medical Center
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Publication
Featured researches published by Jeff Bailey.
Stem Cells | 2005
Michael Jansen; Feng-Chun Yang; Jose A. Cancelas; Jeff Bailey; David A. Williams
The hematopoietic‐specific Rho GTPase, Rac2, regulates a variety of cellular functions including cell shape changes, motility, integrin‐dependent adhesion, and apoptosis. In the study reported here, we demonstrate that wild‐type (WT) hematopoietic stem cells/progenitors (HSC/P) preferentially engraft in nonablated Rac2−/− bone marrow. In addition, primitive Rac2−/− HSC/P transplanted into lethally irradiated WT recipients showed a significant competitive defect compared with WT cells. These defects appeared to be related to HSC/P‐intrinsic defective microenvironment interactions, since Rac2−/− cells showed less adhesion to the femur bone marrow density 1 (FBMD‐1) stromal cell line, a lower frequency of cobblestone area–forming cells, and lower performance in long‐term marrow cultures in vitro when compared with WT cells. In contrast, primitive Rac2−/− hematopoietic cells exhibited normal progenitor colony formation in semisolid medium in vitro and normal proliferation in the steady state in vivo when compared with WT cells. Taken together, these data suggest that Rac2−/− stem/progenitor cells exhibit abnormal interaction with the hematopoietic microenvironment, which leads to defective long‐term engraftment.
Cancer Research | 2008
Michael D. Milsom; Moran Jerabek-Willemsen; Chad E. Harris; Axel Schambach; Emily Broun; Jeff Bailey; Michael Jansen; David Schleimer; Kalpana Nattamai; Jamie Wilhelm; Amanda J. Watson; Hartmut Geiger; Geoffrey P. Margison; Thomas Moritz; Christopher Baum; Jürgen Thomale; David A. Williams
Retroviral-mediated delivery of the P140K mutant O(6)-methylguanine-DNA methyltransferase (MGMT(P140K)) into hematopoietic stem cells (HSC) has been proposed as a means to protect against dose-limiting myelosuppressive toxicity ensuing from chemotherapy combining O(6)-alkylating agents (e.g., temozolomide) with pseudosubstrate inhibitors (such as O(6)-benzylguanine) of endogenous MGMT. Because detoxification of O(6)-alkylguanine adducts by MGMT is stoichiometric, it has been suggested that higher levels of MGMT will afford better protection to gene-modified HSC. However, accomplishing this goal would potentially be in conflict with current efforts in the gene therapy field, which aim to incorporate weaker enhancer elements to avoid insertional mutagenesis. Using a panel of self-inactivating gamma-retroviral vectors that express a range of MGMT(P140K) activity, we show that MGMT(P140K) expression by weaker cellular promoter/enhancers is sufficient for in vivo protection/selection following treatment with O(6)-benzylguanine/temozolomide. Conversely, the highest level of MGMT(P140K) activity did not promote efficient in vivo protection despite mediating detoxification of O(6)-alkylguanine adducts. Moreover, very high expression of MGMT(P140K) was associated with a competitive repopulation defect in HSC. Mechanistically, we show a defect in cellular proliferation associated with elevated expression of MGMT(P140K), but not wild-type MGMT. This proliferation defect correlated with increased localization of MGMT(P140K) to the nucleus/chromatin. These data show that very high expression of MGMT(P140K) has a deleterious effect on cellular proliferation, engraftment, and chemoprotection. These studies have direct translational relevance to ongoing clinical gene therapy studies using MGMT(P140K), whereas the novel mechanistic findings are relevant to the basic understanding of DNA repair by MGMT.
Blood | 2009
Michael D. Milsom; Bernhard Schiedlmeier; Jeff Bailey; Mi-Ok Kim; Dandan Li; Michael Jansen; Abdullah Mahmood Ali; Michelle Kirby; Christopher Baum; Leslie J. Fairbairn; David A. Williams
Ectopic delivery of HOXB4 elicits the expansion of engrafting hematopoietic stem cells (HSCs). We hypothesized that inhibition of tumor necrosis factor-alpha (TNF-alpha) signaling may be central to the self-renewal signature of HOXB4. Because HSCs derived from Fanconi anemia (FA) knockout mice are hypersensitive to TNF-alpha, we studied Fancc(-/-) HSCs to determine the physiologic effects of HOXB4 on TNF-alpha sensitivity and the relationship of these effects to the engraftment defect of FA HSCs. Overexpression of HOXB4 reversed the in vitro hypersensitivity to TNF-alpha of Fancc(-/-) HSCs and progenitors (P) and partially rescued the engraftment defect of these cells. Coexpression of HOXB4 and the correcting FA-C protein resulted in full correction compared with wild-type (WT) HSCs. Ectopic expression of HOXB4 resulted in a reduction in both apoptosis and reactive oxygen species in Fancc(-/-) but not WT HSC/P. HOXB4 overexpression was also associated with a significant reduction in surface expression of TNF-alpha receptors on Fancc(-/-) HSC/P. Finally, enhanced engraftment was seen even when HOXB4 was expressed in a time-limited fashion during in vivo reconstitution. Thus, the HOXB4 engraftment signature may be related to its effects on TNF-alpha signaling, and this pathway may be a molecular target for timed pharmacologic manipulation of HSC during reconstitution.
Cancer Research | 2000
Susanne Ragg; Meng Xu-Welliver; Jeff Bailey; Maria D'souza; Ryan J. Cooper; Saurabh Chandra; Roopa Seshadri; Anthony E. Pegg; David A. Williams
Blood | 2006
Gabriel Ghiaur; Andrew W. Lee; Jeff Bailey; Jose A. Cancelas; Yi Zheng; David A. Williams
Blood | 2008
Gabriel Ghiaur; Michael J. Ferkowicz; Michael D. Milsom; Jeff Bailey; David P. Witte; Jose A. Cancelas; Mervin C. Yoder; David A. Williams
Blood | 2002
Wen Tao; Marie-Dominique Filippi; Jeff Bailey; Simon J. Atkinson; Bret A. Connors; Andrew P. Evan; David A. Williams
Molecular Therapy | 2007
Elke Will; Jeff Bailey; Todd Schuesler; Ute Modlich; Brenden Balcik; Ben Burzynski; David P. Witte; Gerlinde Layh-Schmitt; Cornelia Rudolph; Brigitte Schlegelberger; Christof von Kalle; Christopher Baum; Brian P. Sorrentino; Lars M. Wagner; Patrick Kelly; Lilith Reeves; David A. Williams
Blood | 2007
Lars U.W. Müller; Michael D. Milsom; Chad E. Harris; Jeff Bailey; David A. Williams
Blood | 2005
Gabriel Ghiaur; Michael J. Ferkowicz; Jeff Bailey; Mervin C. Yoder; David A. Williams