The hematological disorders of mice lacking heme oxygenase 1 (HO-1) include hypoferremia, tissue accumulation of iron, and anemia by 20 weeks of age. In a rare human case, HO-1 deficiency was accompanied by anemia, growth retardation, leukocytosis, thrombocytosis, coagulation abnormality, and death at an early age. These disorders in mice and human suggest an important role of HO-1 in hematopoiesis, and that a thorough investigation into the role of HO-1 is warrented. Our preliminary data indicate that there is a severe hematopoietic defect intrinsic to HSC in HO-1 deficient mice, associated with increased frequency of HSCs and progenitors in BM under steady-state condition and accelerated cell division of primitive cells after adoptive transfer, suggesting a rather unique and complexed molecular mechanism. We hypothesize that 1) HO-1 is essential for normal HSC functions and hematopoiesis. In the absence of HO-1, HSCs will be defective and hematopoiesis will be severely impaired in producing mature blood cell of all lineages, especially under hematopoietic stress; 2) this protective role of HO-1 is achieved by regulating the complex balance between quiescence, self-renewal, and differentiation of HSCs, and that loss of HO-1 leads to over-recruitment of HSCs from G0 into G1, and drives the HSCs toward differentiation over self-renewal, leading to ultimate depletion of the HSC pool. To test this hypothesis, I have proposed three specific aims: 1) Characterize the hematopoietic defect in HO-1 deficient mice, and evaluate its severity; 2) Investigate the essential role of HO-1 in the function of HSCs and progenitors, evaluate the affect of HO-1 deficiency on lineage development; 3) Analyze the quiescence, cell cycle status, and cell cycle modulator levels of HSCs under normal and myeloablation conditions. Understanding the HO-1 deficiency associated hematopoetic defect may reveal a unique pathway for regulating the balance between HSC self-renewal and differentiation and hematopoiesis, and eventually lead to more effective therapies for certain types of hematological diseases and more efficient protocols for bone marrow transplantation
| Zhang, Chunyan; Lou, Jingwei; Li, Nainong et al. (2007) Donor CD8+ T cells mediate graft-versus-leukemia activity without clinical signs of graft-versus-host disease in recipients conditioned with anti-CD3 monoclonal antibody. J Immunol 178:838-50 |
