title: A complex MLL rearrangement identified five years after initial MDS diagnosis results in out-of-frame fusions without progression to acute leukemia.
abstract: Chromosomal rearrangements of the MLL gene are uncommon in myelodysplastic syndromes (MDSs), and few studies of their molecular structures and oncogenic mechanisms exist. Here, we present a case of de novo MDS with a normal karyotype at initial diagnosis and a mild clinical course. Five years after the initial diagnosis, investigators identified a complex rearrangement of the MLL gene without progression to acute leukemia. The 5' part of the MLL gene is fused out of frame with the LOC100131626 gene, and the 3' part of the MLL gene out of frame with the TCF12 gene. Rapid amplification of complementary DNA 3' ends yielded two main fusion transcripts, which is in concordance with the two described isoforms of the LOC100131626 gene. For both isoform-fusion transcripts, the open reading frame terminates shortly after the breakpoint that is predicted to form two de facto truncated MLL proteins and disrupts the open reading frame of the LOC100131626, TCF12, and UBE4A genes. Neither dimerization nor a transcriptional activation domain, each of which is causally linked to MLL protein-mediated transformation, is present. This and other unusual MLL rearrangements probably represent a subclass of MLL gene abnormalities that have intrinsically no ability or only a weak ability to transform hematopoeitic cells and are identified only in the context of other hematopoetic malignancies.
authors.affiliation: Diagnostic Center of Acute Leukemia, Institute of Pharmaceutical Biology, The Center for Drug Research, Development, and Safety (ZAFES), Goethe-University of Frankfurt, Frankfurt am Main, Germany. claus.meyer@em.uni-frankfurt.de
authors.forename: Claus
authors.initials: C
authors.lastname: Meyer
authors.forename: Eric
authors.initials: E
authors.lastname: Kowarz
authors.forename: Sze-Fai
authors.initials: SF
authors.lastname: Yip
authors.forename: Thomas Shek-Kong
authors.initials: TS
authors.lastname: Wan
authors.forename: Tai-Kwong
authors.initials: TK
authors.lastname: Chan
authors.forename: Theo
authors.initials: T
authors.lastname: Dingermann
authors.forename: Li-Chong
authors.initials: LC
authors.lastname: Chan
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
mesh_terms: D000208:Acute Disease; D000368:Aged; D018450:Disease Progression; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*
chemical_list: C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase