The MLL recombinome of acute leukemias in 2017

Abstract

<p>Chromosomal rearrangements of the human <i>MLL/KMT2A</i> gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the <i>MLL</i> gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different <i>MLL</i> rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the <i>MLL</i> gene. We observed an age-dependent breakpoint shift with breakpoints localizing within <i>MLL</i> intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in <i>MLL</i> intron 9 predominate in AML or older patients. The molecular characterization of <i>MLL</i> breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the <i>MLL</i> gene with clinical outcome. This study provides a comprehensive analysis of the <i>MLL</i> recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.<br /></p>