What Is New? An Update of the MLL Recombinome Including the Three Novel Partner Genes ABI2, PDS5A, and TOP3A

Abstract 1351

Chromosomal rearrangements of the MLL gene are associated with pediatric and adult de novo as well as therapy related acute myeloid leukemias, acute lymphoid leukemias, biphenotypic leukemias, and myelodysplastic syndromes. So far more than 70 MLL fusion partner genes have been characterized at the molecular level involving nearly all chromosomes. Though 11q23 rearrangements are associated with high-risk leukemias the clinical outcome of MLL rearrangements depends highly on the specific fusion partner involved. Nearly 40% of these partner genes have been identified at the Diagnostic Center of Acute Leukemia (DCAL) including the novel partner genes ABI2, PDS5A and TOP3A by analyzing more than 1400 MLL rearrangements. These rearrangements from 27 different countries include 52 different partner genes. This overview indicates all the specific introns of the translocation partner genes (TPGs) found to be involved in MLL translocations, their chromosomal locations and the type of genetic abnormality that is leading to the MLL fusion. More than 20% of all MLL rearrangements are complex ones. Within these complex rearrangements, the 5' part of the MLL gene is generally fused in frame to one of the most frequent partner genes. But the 3' part of the MLL gene is fused in many cases to a novel so-called “reciprocal MLL partner gene” like DENND4A or LRRTM4. To date more than 90 reciprocal MLL partner genes have been identified. In addition we present a recently analysed 4-way translocation where all four breakpoints could be identified by systematic breakpoint analysis using LDI-PCR. Also three novel “spliced MLL fusions”, a mechanism to generate functional chimeric fusion transcripts, involving MLLT4 (AF6), MYO1F, and CT45A2 have been identified at the DCAL. With these results, the number of genes involved in „spliced MLL fusions“ has increased from eight to eleven. Moreover we present the current breakpoint cluster region (bcr) for the 14 most frequent partner genes, namely AFF1 (AF4), MLLT3 (AF9), MLLT1 (ENL), MLLT10 (AF10), MLLT4 (AF6), ELL, EPS15, MLLT6 (AF17), SEPT6 (AF17), MLLT11 (AF1Q), SEPT9, AFF3 (LAF4), TET1, SEPT5 (PNUTL) and partial tandem duplications. For six patients, no partner gene could be identified at the molecular level and for 5 patients the identified fusion is out of frame. Unfortunetely all attemps to identify functional chimeric fusion transcripts by RACE and RT-PCR failed. These unusual MLL rearrangements probably represent a subclass of MLL abnormalities which have per se no or only a weak ability to transform hematopoeitic cells and are indentified only in the context of other hematopoeitic malignancies like the recently described MLL partner SACM1L. Finally, the determined patient-specific fusion sequences are succesfully used worldwide for minimal residual disease (MRD) monitoring to improve the treatment and outcome of acute leukemia patients.