Is APL the result of a failure of senescence as a tumor suppressor mechanism?
As discussed above the current model of the origin of APL is largely based on the proposal that RAR fusion proteins repress RA-responsive genes required for myeloid cell differentiation. The discovery that PML regulates senescence suggests a new scenario for the development of APL that does not exclude previously proposed models of the disease (Figure 2b). In this model a mutation or an abnormal bone marrow microenvironment102 might initiate uncontrolled proliferation, which eventually can trigger the induction of premature senescence. In most individuals this mechanism will suffice to remain free of leukemic disease. However, in a few cases mutated cells will escape senescence in a process associated to chromosomal abnormalities including the balanced reciprocal translocations observed in all cases of APL. This scenario is consistent with recent studies where mammary epithelial cells in culture escaped senescence in association with chromosomal aberrations.103 It is also consistent wi
