In full-blown AML (A), the T cells directed against the leukemia antigens cannot bring about enough lysis of leukemic (stem) cells to bring the disease under control. This is due to the fast dynamics and immunosuppressive mechanisms of AML. Chemotherapy strongly suppresses the leukemic cells and usually allows normal hematopoietic cells to reappear in sufficient numbers (B-C). Chemotherapy can also stimulate the immune response, which may be effective in lysing leukemic cells and stem cells, but usually this is not effective enough to eradicate (minimal) residual disease persisting in a majority of AML cases. In NPM1^mut AML (C), especially NPM1^mutFLT3-ITD^neg AML, it is hypothesized here that T cells, directed against leukemia antigens—especially mutated NPM1—and activated by immunogenic chemotherapy, may be powered enough to bring about complete eradication of AML by lysing all remaining residual leukemic (stem) cells. In case of minimal residual disease (B), complete eradication of leukemic (stem) cells can be brought about by immunotherapy (D). Examples of clinically effective immunotherapy include allogeneic hematopoietic stem cell transplantation followed or not by donor lymphocyte infusions, and vaccination with tumor antigen peptides or with dendritic cells loaded with tumor antigens. Successful immunotherapy against AML has been associated with an increase of T lymphocytes reacting against the leukemia antigens. Leukemia antigens may be present on the surface of normal hematopoietic cells, but these seem to be less susceptible to lysis by antigen-specific T cells. The leukemia antigens present on leukemic cells may be similar to or different from those on normal hematopoietic cells. They are then designated, respectively, as leukemia-associated and leukemia-specific antigens. The cell numbers and leukemia antigen distribution and density indicated in this figure are for schematic purposes only. Professional illustration by Paulette Dennis.