Covert preleukemia driven by MLL gene fusion

Acute leukemia is considered to be a two- or multiple-step process. Although there is a considerable knowledge regarding the character of the "first hit," the nature of the "second hit" remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential "second hit" precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.