The HumanMLLGene: Nucleotide Sequence, Homology to theDrosophila trxZinc-Finger Domain, and Alternative Splicing

Abstract

We have previously reported the cloning of several cDNAs corresponding to the MLL gene. The predicted primary amino acid sequence of two of these clones, 14p-18B and 14-7, reveals nearly complete identity with parts of the sequences of HRX, ALL-1, and Htrx-1, including a Zinc-finger region with homology to the Drosophila trithorax gene. However, we found that there is a stretch of 39 amino acids that is absent from 14p-18B when compared to ALL-1 and HRX. Another sequence of three amino acids is present in ALL-1, but is absent from 14p-18B and HRX. Nucleotide sequence examination reveals that these differences arise from alternative splicing, suggesting that MLL, HRX, and ALL-1 each represents a different alternative splicing product from the same gene. At least two cDNA clones, 14-7 and 14p-18C, correspond to incompletely processed transcripts including intron sequences. Northern blots using a subclone of 14p-18B revealed mRNA species of 14-16 kb in size in various human tissues. RNase protection assays show that the splice variant containing exon 8 and lacking a 9-bp extension 3' of exon 12 is predominantly expressed in hematopoietic cell lines.

Cryptic insertion of MLL gene into 9p22 leads to MLL–MLLT3 (AF9) fusion in a case of acute myelogenous leukemia

“…These PCR products were similar in size to those seen in patients in a study of Super et al (1997). Alternative splicing and exon scrambling have been reported for the MLL gene (Mbangkollo et al, 1995;Caldas et al, 1998) and may extend to MLL fusion genes. The PCR product from the ins(9;11) patient was directly sequenced using the primers described above.…”

Histone H3 lysine 4 (H3K4) methylation in development and differentiation

“…The Mll gene (also called ALL-1 and HRX) was discovered by virtue of its involvement in human acute leukemia; chromosome rearrangements involving a breakpoint within the MLL gene are associated with a variety of acute myeloid and lymphoid leukemias (Djabali et al, 1992; Gu et al, 1992; Mbangkollo et al, 1995; Tkachuk et al, 1992). While MLL is structurally homologous to Drosophila TRX, it also contains three AT-hook domains and a DNA methyltransferase homology domain that are absent from TRX.…”

Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia

“…A complex pattern of alternative splicing with exon scrambling has been reported for the MLL gene in both normal and malignant cells. [40][41][42] Alternative splicing and cryptic splice site activation during RNA processing of MLL-AF4 chimeric transcripts has been observed. 43 Recently, splice variants for MLL-MLLT10 fusion transcripts were also reported by Angioni et al 11 Clearly, alternative splicing of the normal MLL gene may result in increased complexity of the biological function of MLL and possibly the same holds for the splice variants of the hybrid transcripts.…”