DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4

The pathogenesis of Infant ALL is still not well defined. Short latency to leukemia and very high concordance rate for ALL in MLL-positive infant twins suggest that the MLL rearrangement itself could be sufficient for overt leukemia. Attempts to generate a suitable mouse model for MLL-AF4 positive ALL did not thoroughly resolve whether cooperating mutations are required to reduce latency and generate overt leukemia in vivo. In this study, we applied SNP-array technology to perform genomic profiling of 28 Infant ALL cases carrying t(4;11) with the purpose to detect MLL-cooperating aberrations hidden to conventional techniques and gain new insights into Infant ALL pathogenesis. In contrast to pediatric, adolescent and adult ALL cases, MLL rearrangement in Infant ALL is associated to an exceptionally low frequency of copy number abnormalities, thus confirming the unique nature of this disease. By contrast, additional genetic aberrations are acquired at disease relapse. Small segmental UPD traits were frequently detected, mostly constitutional, and widely distributed throughout the genome. It can be argued that MLL rearrangement as a first hit, rather than inducing the acquisition of additional genetic lesions, has a major role to drive and hasten the onset of leukemia.