Incidence and Spectrum of MLL Gene Rearrangements in Pediatric Acute Leukemias in Poland

Objectives and aims of the study: The MLL oncogene on chromosome 11q23 undergoes various translocations in acute leukemias. MLL gene rearrangements are associated with worse outcome in infant acute lymphoblastic leukemia (ALL), while t(4;11) is a high-risk factor in children with ALL > 1 year of age. The prognostic value of MLL gene rearrangements in acute myeloid leukemia (AML) remains to be determined. In this study, we aimed at comprehensive analysis of the incidence and spectrum of MLL gene rearrangements in a large cohort of pediatric acute leukemias in Poland.

Material and Methods: The study group comprised 355 children including 271 patients with de novo ALL, 24 children with relapsed ALL, 56 children with AML, three children with relapsed AML and a patient with acute bi-lineage leukemia. The presence of MLL rearrangements was determined with split-signal fluorescent in situ hybridization (FISH). Partner genes rearranged to MLL locus were identified with long-distance inverse PCR at the genomic DNA level.

Results: MLL rearrangements were found in 18 patients with de novo ALL, 12 infants and six children > 1 year of age (6.6%). They included 12 t(4;11) with MLL-AFF1 fusion, two t(11;19) with MLL-MLLT1 fusion, one t(9;11) with MLL-MLLT3 fusion and one t(10;11) translocation with two gene fusions MLL-MLLT10 and PIWIL4-MLL. MLL rearrangements were also present in two patients with relapsed ALL. MLL rearrangement characterized 11 patients with de novo AML [four t(9;11) with MLL-MLLT3 fusion, one t(11;19) with MLL-ELL fusion, one (1;11) with MLL-EPS15 fusion, and a single t(1;11;17)] and one patient with secondary AML after ALL treatment [t(11;19)], which comprises 22% of all AML patients. This incidence is higher than usually described in literature (approximately 10–15%). Interestingly, in patient with t(1;11;17) two in-frame gene fusions were identified: MLL-MLLT11 and MYO18A-MLL, with the latter previously not reported. MLL gene rearrangement [t(9;11)], was also found in one of three relapsed AML cases. In a patient with acute bi-lineage leukemia both lymphoblasts and myeloblasts displayed t(4;11) translocation. Interestingly MLL-AFF1 fusion in this patient was accompanied by the fusion of the distal part of MLL to KIAA0999 gene on chromosome 11q23.3.

Conclusions: In ALL patients MLL gene rearrangements are most frequent in infants (80% of cases) and very infrequent in older children (< 2%). Application of split-signal FISH as a screening for MLL gene rearrangements revealed unprecedentedly high incidence of these aberrations in childhood AML. Molecular analysis of MLL gene fusions and breakpoints shows several different mechanisms leading to these chromosome aberrations.