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. 2024 Jun;38(6):1403-1406.
doi: 10.1038/s41375-024-02261-3. Epub 2024 Apr 27.

The KMT2A/MLL consensus gene structure: a comprehensive update for research and diagnostic implications

C Meyer  1 , P Larghero  1 , B A Lopes  1   2 , R Marschalek  3
Affiliations

The KMT2A/MLL consensus gene structure: a comprehensive update for research and diagnostic implications

C Meyer et al. Leukemia. 2024 Jun.
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The KMT2A gene structure, protein domain structure and important alternative splice variants.
a KMT2A gene structure with percentages of breakpoints in BCR1 and BCR2. b the 5‘-UTR/intron • exon and exon • intron/3’-UTR junctions of all 38 exons. The gene has a maximal open reading frame of 12,096 nucleotides (4032 amino acids), but exhibits also alternative protein variants due to alternative splicing events that may exclude exon 2 or 22, as well as the junction between exon 15 and 16 (4005 aa minus 3/11/14 or 3972 aa minus 3/11/14. c summarizes the alternative splice events at the exon 15/16 junction, leading to functional diverse KMT2A PHD3 domains. The depicted protein structures have been folded in silico by using the SWISS-Model server. d The PHD1-3/BD/extPHD4 domain of KMT2A. Predicted structural folding of the PHD1-3/BD/extPHD4 domains with depicted either the −3 variant of PHD3 (A) or with the additional 27 amino acids encoded by the alternatively spliced exon 22 (B). This changes ZF2a into ZF2b and displays an extended folding below the PHD4 domain structure which remains structurally unchanged, but contains two cysteines. e Structure of the CYP33 bound region, where the position of the BD/extPHD4 domain is changed due to a cis-trans isomerization of a proline residue located between the PHD3 and BD domain. This disables H3K4me3 reading, but allows CYP33 binding and the recruitment of the BMI1 repressor complex to the CXXC domain of KMT2A. All depicted protein domain structures have been folded in silico by using the SWISS-Model server. f KMT2A protein. All domains of the KMT2A protein are depicted. Above the protein structure of 4032 amino acids: exon boundaries for all 38 exons and the known protein binding partners. Below the protein structure: known molecular functions of these protein modules. g Taspase1 cleavage at the 2 Taspase1 cleavages sites (TCS) converts the full-length protein into an N- and C-terminal portion that form a complex with all protein binding partners. The final complex is binding and reading promoters, as well as able to bind, read and write chromatin signatures. If the Polycomb repressor complex (BMI1, HPC2, CtBP and HDAC1) is recruited via the CYP33-induced conformational switch in PHD3, then this protein complex converts from a transcriptional activator to a transcriptional repressor complex.
See this image and copyright information in PMC

References

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