(A) In rare HSPCs, HOXB4-containing vectors integrate near protooncogenes and the influence of the vector’s strong promoter deregulates their expression, favoring the engraftment and proliferation of these clones over those without activated protooncogenes. The additional expression of HOXB4 may give these clones further proliferative advantage compared with those without HOXB4. These expanded clones subsequently enter a dormant phase (the latency period), when new mutations accumulate in their genome. This increased tendency to accumulate DNA damage may be related to the deregulated expression of protooncogenes within these clones. Multiple-hit models of tumorigenesis predict that the higher number of cells initially expanded under the influence of HOXB4 increases the likelihood that one or several of these cells will acquire an additional mutation (M), leading to uncontrolled clonal expansion and overt leukemia. (B) In the absence of HOXB4 or similar growth-promoting genes in the gene transfer vector (for example, with vectors containing the drug selection gene methylguanine methyltransferase [MGMT], as used in the study in this issue by Zhang et al.; ref. 19), integration near protooncogenes is possible, leading to their deregulation due the influence of the vector’s strong promoter. However, in the absence of cooperativity from HOXB4 (or other growth-promoting genes) in the gene-transfer vector, initial proliferation of these clones is less pronounced and, therefore, the risk that one or several of these cells will acquire an additional mutation, leading to uncontrolled clonal expansion and overt leukemia, is lower.