“Slot machine” model of leukemogenesis. Alterations in signaling molecules, transcription factors (TFs), epigenetic regulators (ERs), tumor suppressors (TSG), spliceosome components and various genome abnormalities (examples are given) fall into (at least) four “reels” (steps) that combine to induce a malignant myeloid disease. Acute myeloid leukemia (AML) results from one of the allowed combinations of four (at least) cooperating alterations. At chronic stages, the steps are variably combined, some may be absent (e.g. signaling), some may be specific (e.g. SF3B1 splicing mutations in RARS). Each step can be achieved by alterations in one of several genes. The initial step leads to expansion of a founding clone. Two examples of draw (plain and dotted lines) leading to AML are shown.