The MLL recombinome of acute leukemias in 2013

Abstract

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Mutation-Profile-Based Methods for Understanding Selection Forces in Cancer Somatic Mutations: A Comparative Analysis

“…Some cancer genes also show negative selection in cancer genomes, such as the oncogene MLLT3 (C N /C S = 0.11, p = 3.14 × 10 ). The MLL-MLLT3 gene fusion is the main mutation type of MLLT3 that drives tumorigenesis in acute leukemia [37]. Interestingly, MLLT3 has recurrent synonymous mutations at amino acid positions 166 to 168 (S166S, 8/9155; S167S, 33/9155; S168S, 23/9155).…”

Genetically engineered mouse models of human B-cell precursor leukemias

“…More than 50 different translocations have been identified in which MLL is involved, and the most frequent ones in pB-ALL (80% of the cases in which the MLL gene is involved in pB-ALLs) are those affecting the genes AF4, AF9, ENL, AF10 and AF6 (ref. 62). Contrary to what we have described until now, in MLL-related ALLs, additional genetic alterations are uncommon (although alterations in FLT3 expression are frequently seen in MLL-based leukemias 63 ), suggesting that all the changes necessary for leukemogenesis are directly or indirectly driven by the oncogene.…”

Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

“…More than 98% of breakpoints within the MLL1 gene are located within an 8.3-kb breakpoint cluster region between exons 8 and 13 (Meyer et al 2013) that has multiple topoisomerase II cleavage sites as well as nuclear matrix attachment regions. Interference with normal cellular processes such as therapeutic inhibition of topoisomerase II leads to the formation of chromosomal rearrangements found in leukemia (Strissel et al 1998).…”

“…1) (Krivtsov and Armstrong 2007). Currently, more than 70 translocation partner genes have been reported; however, four (AF4, AF9, AF10, ENL) account for .75% of cases (Meyer et al 2013). …”