NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biological Considerations of Hematological Relapse following Allogeneic Stem Cell Transplantation Unrelated to Graft-versus-Tumor Effects: State of the Science  Mitchell S. Cairo, Craig T. Jordan, Carlo C. Maley, Clifford Chao, Ari Melnick, Scott A. Armstrong, Warren Shlomchik, Jeff Molldrem, Soldano Ferrone, Crystal Mackall, Laurence Zitvogel, Michael R. Bishop, Sergio A. Giralt, Carl H. June  Biology of Blood and Marrow Transplantation  Volume 16, Issue 6, Pages 709-728 (June 2010) DOI: 10.1016/j.bbmt.2010.03.002 Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 The neoplastic cells in an allogenic stem cell transplant patient go through 3 regimes of selection. During neoplastic progression, clones with evolutionary neutral mutations (in gray), which have no effect on survival or reproduction of the clone, expand and contract randomly. Inactivation of tumor suppressor genes and activation of oncogenes often drive clonal expansions (clones in shades of yellow, red, and blue). Ablation introduces a new selective pressure on the neoplastic cells, which may kill most of them, but some clones may survive (blue clone) and continue to generate subclones (shades of purple and green). The allogenic immune cells then introduce a third selective regime in the graft-versus-tumor reaction. If there is a clone that can escape the allogenic immune response (the green clone), minimal residual disease may remain, which can eventually lead to relapse, possibly through additional somatic evolution. Thus, relapse derives from clones that have survived the different selective pressures of both ablation and the graft-versus-tumor immune response. Biology of Blood and Marrow Transplantation 2010 16, 709-728DOI: (10.1016/j.bbmt.2010.03.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Proposed model of the developmental hierarchy in the development of acute myelogenous leukemia, similar to normal hematopoiesis. Biology of Blood and Marrow Transplantation 2010 16, 709-728DOI: (10.1016/j.bbmt.2010.03.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Proposed model of progression from committed hematopoietic stem cell progenitor cells transformed by an oncogene MLL-AF9 into a leukemia stem cell (LSC). Biology of Blood and Marrow Transplantation 2010 16, 709-728DOI: (10.1016/j.bbmt.2010.03.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Proposed model of the balance of genetic and epigenetic content in the progression of tumor stem cells to a malignant phenotype. Biology of Blood and Marrow Transplantation 2010 16, 709-728DOI: (10.1016/j.bbmt.2010.03.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions