MLL gene rearrangements were detected with a single probe and a single restriction-enzyme digest in all DNA samples from patients with the common 11q23 translocations as well as in 16 patients or cell lines with other 11q23 anomalies. The ability to detect an MLL gene rearrangement rapidly and reliably, especially in patients with limited material for cytogenetic analysis, should make it possible to identify patients who have a poor prognosis and therefore require aggressive chemotherapy or marrow transplantation.

Recurring chromosomal abnormalities Involving translocations at chromosome 11 band q23 are associated with human myelold and lymphold leukemia as well as lymphoma. We have Identified the gene located at this breakpoint and have named it MLL (for myeloidlymphold, or mixed-lineage, leukemia). The t(4;11), t(6;11), t(9;11), and t(11;19) are among the most common reciprocal translocathons in leukemia cells involving this chromosomal band. We now have evidence that the breakpoints in all of these translocations are clustered within a 9-kilobase (kb) BamHI genomic region of the MLL gene. By Southern blot hybridization using a 0.7-kb BamEH cDNA fgnt of the MLL gene called MLL 0.7B, we have detected rearrangements of DNA from cell ln and patient material with an 11q23 trandocation in this region.Northern blot analyses dicte that this gene has multipl cpts, some of which appear to be lineage-specific. In normal pre-B cells, four transcripts of 12.5, 12.0, 11.5, and 2.0 kb are detected. These tanscripts are also present in monocytoid cell lines with additional hybridization to a 5.0-kb t rpt, indicating that expression of different-sized MLL transcripts may be associated with normal hematopoietic lineage development. In a cell Hlne with a t(4;11), the expression of the 12.5-, 12.0-, and 11.5-kb transcripts is reduced, and there is evidence of three other altered transcripts of 11.5, 11.25, and 11.0 kb. Thus, these 11q23 translocations result in rearrangements of the MLL gene and may lead to altered function(s) of MLL and of other gene(s) involved in the translocation.Nonrandom translocations involving chromosome 11 band q23 occur frequently in both myeloid and lymphoblastic leukemias (1, 2). The four most common reciprocal translocations are t(4;11) and t(11;19), which often exhibit either lymphoblastic and/or monocytic markers, and t(6;11) and t(9;11), which are mainly found in monoblastic and/or myeloblastic leukemias (3). Other chromosomes which are involved in recurring translocations with this band in acute leukemias are chromosomes X, 1, 2, 10, and 17. Fluorescence in situ hybridization showed that a yeast artificial chromosome containing the CD3D and CD3G genes was split in cells with the four most common translocations (4). We identified the gene located at the breakpoint and we named it MLL (5). Recent data indicate that the breakpoint in a cell line, RC-K8, with a t(11;14)(q23;q32) is -110 kilobases (kb) telomeric to the breakpoint in other 11q23 translocations which involve the MLL gene (6)(7)(8). Our data support this finding and suggest that there are at least two different regions of band q23 involved in chromosome 11q23 translocations; we distinguish these by using the term "more centromeric" to designate MLL rearrangements from those involving the more telomeric breakpoint, which has been described as the rck locus (6) and the p54 gene (7).By pulsed-field gel electrophoresis analyses, the breakpoint region in MLL was mapped to a 92-kb Not I fragment -=100 kb telomeric to the CD3G gene. Nonrepetitiv...

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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.

Saccharomyces cerevisiae