Cloning of cDNAs of the MLL gene that detect DNA rearrangements and altered RNA transcripts in human leukemic cells with 11q23 translocations.

Abstract

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...

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)

“…In acute leukemias at least 29 di erent chromosome translocations a ect the region 11(q23) (Rowley, 1993). The vast majority of these breaks disrupt the mixed-lineage leukemia (MLL) gene within a small region of 8.6 kb (McCabe et al, 1992) and fuse it to a variety of di erent partner genes. To date, at least 10 of these fusion partners have been identi®ed and molecular genetically characterized (Rowley, 1993).…”

MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein

“…T he MLL (mixed-lineage leukemia) gene located on chromosome band 11q23 is involved in many chromosomal translocations associated with acute leukemia (1)(2)(3)(4)(5). MLL is involved in translocations with Ͼ40 different genes, and breakpoints in MLL fall in an 8.3-kb breakpoint cluster region (refs.…”

MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3)

“…5C). The breaks in MLL fall within the previously described 8.3-kb genomic BCR (8,44). The location of the breaks within CBP span a very large genomic region that consists mainly of one intron.…”