Chromosomal rearrangements of the human MLL/KMT2A 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 MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL 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 MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL 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.

Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH þ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH þ patients showed a better early response to chemotherapy as compared with NOTCHÀ patients, according to the rate of poor pre-phase 'responders' (25% versus 44%; P ¼ 0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P ¼ 0.01) at completion of induction. However, the outcome of NOTCH þ patients was similar to that of NOTCHÀ patients, with a 5-year event-free survival (EFS) of 73% and 70% (P ¼ 0.82), and 5-year overall survival of 82% and 79% (P ¼ 0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH þ ) versus 42% (NOTCHÀ), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH þ ) versus 78% (NOTCHÀ). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1 þ patients (8.3%), which could be related to a higher propensity of NOTCH þ leukemic blasts to target the CNS.