The contribution of the GM to the multistep developmental hypothesis for leukemogenesis. In intrinsically predisposed subjects, preleukemic clones may arise and, according to the hypothesis, their development may be influenced by environmental stimuli. The GM can represent one of these, serving as an additional hit in the multistep process, as was demonstrated in patients at the time of diagnosis (right). Conversely, an “intact” GM and/or the absence of interaction with common pathogens may protect genetically predisposed subjects (left).