The KMT2A/MLL consensus gene structure: a comprehensive update for research and diagnostic implications
C Meyer, Patrizia Larghero, BA Lopes, Rolf Marschalek
Abstract
The KMT2A gene holds significant importance in both basic research and clinical diagnosis due to its involvement in numerous chromosomal translocations. To date, a total of 112 such translocations have been identified at the molecular level, all linked with the onset of acute leukemias presenting different disease phenotypes (ALL, AML, MPAL) [ 1 ]. The KMT2A gene, initially identified as the MLL gene located at chromosomal position 11q23 [ 2 ], was subsequently characterized by several other laboratories in 1992 and 1993. Due to its homology with the Drosophila Trithorax protein, it was designated as the “Trithorax-like gene” [ 3 ], “ALL-1” [ 4 ], and the human homolog of Drosophila Trithorax, “HRX” [ 5 ]. In 1996, two independent labs elucidated the complete gene structure of KMT2A . Using cloned radiolabeled cDNAs, Carlo Croce’s and our laboratory generated slightly differing provisional gene structures [ 6 , 7 ]. Notably, the presence or absence of KMT2A exon 2 varies in public databases (NCBI: NG_027813; ENSEMBL: ENSG00000118058). However, a quantitative RNA-Seq data analysis demonstrated that KMT2A exon 2, spanning only 99 bp, is as frequently observed in RNA-Seq data as neighboring KMT2A exons 1 (431 bp) and exon 3 (70 bp), indicating that it is rarely spliced out. ENSEMBL lists exon 2 only in two full-length transcripts of KMT2A (ENST00000531904 and ENST00000649666). In addition to the discrepancies concerning KMT2A exon 2, a recent experimental analysis unveiled a previously unidentified “exon 22” situated within intron 21 of KMT2A . This newly discovered KMT2A exon 22 has been documented in the ENSEMBL database (ENST00000691053), indicating its potential incorporation into rare and alternatively spliced transcripts. Since public databases do not yet faithfully represent the correct KMT2A gene structure, we advocate for an updated KMT2A gene structure comprising a total of 38 exons for the scientific community. Additionally, we provide precise nucleotide positions of all KMT2A exons and introns on chromosome 11, based on the GRCh38/hg38 human reference genome, in a Supplementary Data File .