This annual report is abbreviated due the unexpected death of Dr. Sloand, who is largely responsible for work in this area. Efforts in myelodysplasia were in three areas: 1. Clinical trials, directed mainly towards immunomodulatory therapy of low risk myelodysplastic syndrome;2. Investigation of the mechanism for hematologic response to immunosuppressive therapy, using in vitro methods;3. Laboratory studies of the role of inflammation in inducing chromosome instability, such as aneuploidy. Additionally, the Branch has performed clinical studies of an inhibitor of cyclin D, ON1910, in selected patients with high risk MDS. In clinical studies, we completed protocols examining the utility of alumtuzimab (Campath;a monoclonal antibody directed to CD52) in patients selected for a high probability of response to immunosuppression. The probability algorithm was based on our extensive experience with horse ATG plus cyclosporine in patients with MDS. In our recently published study, almost 80% of 22 patients who were mainly younger and HLADR15 showed a clinically meaningful hematologic response to alemtuzimab. In addition to achieving transfusion-independence and adequate white blood cell counts, several patients also surprisingly showed reversion of abnormal cytogenetics to normal, for unexplained reasons. Based on our ATG experience and that of others plus this new trial of alemtuzimab, immunosuppressive therapy would appear appropriate for selected patients with MDS, in whom it can induce hematologic response and prolonged survival. In other clinical studies, ON1910 was tested in MDS patients with more advanced disease. The drug, which has also been studied in lymphoma, did lead to transient hematologic improvement in some patients without pronounced toxic effects. Ancillary studies showed that ON1910 achieved the expected molecular effects on cells in vivo. In the laboratory, extensive work directed to the mechanism of immune cell suppression of hematopoiesis in the trisomy 8 form of MDS were completed with the publication of experiments showing that at least one target of cytotoxic lymphocytes in this syndrome is a WT1 androgen. WT1 is known tumor antigen, expressed in both normal stem cells and at higher levels in some leukemic cells. Our experiments suggest a mechanism in trisomy 8 of WT1 over expression, probably secondary to a gene dosage effect of c-myc (located on trisomy 8), leading to immune cell recognition, innocent bystander killing of normal hematopoietic cells, and evolution of a trisomy 8 clone resistant to apoptosis. Relief of immune-mediated cell killing by biological agents such as ATG and Campath can relieve normal hematopoiesis and improve blood counts. In separate laboratory experiments, we have pursued more generally the relationship between inflammation and chromosome instability. In these experiments, the total lymphocytes or lymphocyte subpopulations (separated CD4 and CD8 cells) were added to autologous or HLA-mismatched target bone marrow cells. After several days of exposure, the bone marrow cells were assessed for evidence of chromosome instability, using in situ hybridization. These experiments have suggested that exposure to HLA-mismatched effector cells leads to an increase in aneuploid cells, mainly monosomy 7 but also trisomy 8. This effect is mediated by CD8 rather than CD4 cells and enhanced by a cytokine such as gamma-interferon. Current experiments are directed towards obtaining more robust and confirmatory data and discerning a mechanism, especially the possibility that accelerated telomere attrition occurs as a result of increased T cell proliferation under lymphocyte attack.

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Fan, Jianjia; Shimizu, Yoko; Chan, Jeniffer et al. (2013) Hormonal modulators of glial ABCA1 and apoE levels. J Lipid Res 54:3139-50
Keyvanfar, Keyvan; Weed, Jason; Swamy, Prashanth et al. (2012) Interphase Chromosome Flow-FISH. Blood 120:e54-9
Olnes, Matthew J; Poon, Andrea; Miranda, Susan J et al. (2012) Effects of granulocyte-colony-stimulating factor on Monosomy 7 aneuploidy in healthy hematopoietic stem cell and granulocyte donors. Transfusion 52:537-41
Olnes, Matthew J; Shenoy, Aarthie; Weinstein, Barbara et al. (2012) Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. Leuk Res 36:982-9
Dumitriu, Bogdan; Young, Neal S (2012) Damage control and its costs: BM failure in Fanconi anemia stems from overactive p53/p21. Cell Stem Cell 11:7-8
Sloand, Elaine M; Melenhorst, J Joseph; Tucker, Zachary C G et al. (2011) T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy. Blood 117:2691-9
Sloand, Elaine M; Olnes, Matthew J; Weinstein, Barbara et al. (2010) Long-term follow-up of patients with moderate aplastic anemia and pure red cell aplasia treated with daclizumab. Haematologica 95:382-7
Cheng, Kit L; Brody, Judith; Warshall, Craig E et al. (2010) Paroxysmal nocturnal hemoglobinuria following alemtuzumab immunosuppressive therapy for myelodysplastic syndrome and complicated by recurrent life-threatening thrombosis despite anticoagulation: successful intervention with eculizumab and fondaparinux. Leuk Res 34:e85-7
Scheinberg, Phillip; Marte, Michael; Nunez, Olga et al. (2010) Paroxysmal nocturnal hemoglobinuria clones in severe aplastic anemia patients treated with horse anti-thymocyte globulin plus cyclosporine. Haematologica 95:1075-80
Sloand, Elaine; Pfannes, Loretta; Ling, Casey et al. (2010) Graft-vs.-Host Disease: Role of Inflammation in the development of chromosomal abnormalities of keratinocytes. Biol Blood Marrow Transplant :

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