The normal developmental hierarchy (black arrows) from a stem cell to a mature cell can be corrupted by mutations that lead to the establishment of cancer stem cells (CSCs; red arrows). CSCs may arise from: 1) self-renewing tissue stem cells that improperly respond to or receive abnormal niche signals, 2) progenitor cells that receive abnormal signals to reactivate stem cell programs and self-renewal or 3) differentiated cells that de-differentiate based on abnormal signals to obtain self-renewing ability. Experimental evidence suggests that aberrant expression of PRDM14 is capable of promoting models 1 and 2, but not 3. CLP, common lymphoid progenitor; BPC, breast ductal progenitor cell; EPC, enterocyte progenitor cell.