The Structure of the Human ALL-1/MLL/HRX Gene

Abstract

The human ALL-1/MLL/HRX gene on chromosome 11q23 is the site of many locally clustered chromosomal alterations associated with several types of acute leukemias, including deletions. partial duplications and reciprocal translocations. Structurally variant proteins derived from an altered ALL-1 gene presumably make essential contributions to the malignant transformation of hematopoietic progenitor cells. The ALL-1 gene is spread over approximately 92 kb and consists of at least 37 exons. An exon/intron map including the position of the 3'-end of the gene and a detailed restriction map were produced and an updated map is presented. Data from other laboratories were incorporated where compatible. Exon/intron boundaries were sequenced and an intron-phase analysis was performed. The results are expected to contribute to a better understanding of those structural alterations of the gene that conserve the open reading frame and produce presumably oncogenic variants of the ALL-1 protein. They will also facilitate the rapid molecular diagnosis of structural alterations of this gene and the choice of therapeutic options. Mechanisms that may potentially account for the striking clustering of the translocation breakpoints in the breakpoint cluster region of the gene are discussed.

A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells

“…Breakpoints from patients (circled numbers or letters) were analysed as described in the text and are connected by lines between both breakpoint cluster regions. Numbering of exons of the MLL gene according to Nilson et al (1996) and Marschalek et al (1997); of the AF-4 gene according to Nilson et al (1997) cross-over mechanism could have produced the observed ®nal state. Each of these translocation events was accompanied by deletions, duplications and/or inversions of germline DNA sequences.…”

“…The MLL/AF-4 mRNA of patient PCB contained a fusion of MLL exon 11 to AF-4 exon 4 (nomenclature according Nilson et al, 1996Nilson et al, , 1997Marschalek et al, 1997). The AF-4/MLL mRNA of the same patient showed a fusion of AF-4 exon 3 to MLL exon 12.…”

“…Among the latter are a number of translocations to the MLL gene (Ziemin van der Poel, 1991;Djabali et al, 1992;Gu et al, 1992a;Tkachuk et al, 1992) located on the long arm of human chromosome 11 (band q23). More than 30 di erent chromosomal translocations to the 11q23 region have so far been identi®ed, all of which are associated with hematologic malignancies, and many of the translocation partner loci have been analysed at the molecular level (Bernard and Berger, 1995;Marschalek et al, 1997). In particular, translocations t(4;11) are regularly associated with high-risk infant acute pro-B lymphocytic leukemias and have been proposed to initiate the development of these leukemias (Ford et al, 1993;Bernard and Berger, 1995;Canaani et al, 1995;Marschalek et al, 1997).…”

“…More than 30 di erent chromosomal translocations to the 11q23 region have so far been identi®ed, all of which are associated with hematologic malignancies, and many of the translocation partner loci have been analysed at the molecular level (Bernard and Berger, 1995;Marschalek et al, 1997). In particular, translocations t(4;11) are regularly associated with high-risk infant acute pro-B lymphocytic leukemias and have been proposed to initiate the development of these leukemias (Ford et al, 1993;Bernard and Berger, 1995;Canaani et al, 1995;Marschalek et al, 1997). Thus, the MLL gene is highly promiscuous in its recombinatorial activity, and it is an important objective to identify the molecular mechanisms leading to these translocations.…”

AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14)

“…Unlike other MLL rearrangements previously studied, no extra nucleotides or heptamer-like signals were observed at the junction point, which probably rules out any involvement of VDJ recombinase. It has been shown that large numbers of ALU sequences are present at the MLL breakpoint (Marschalek et al, 1997), which may render this region particularly prone to recombination events. An ALU sequence was found on chromosome 15 660 bp downstream from the breakpoint, which could thus be predisposed to translocation events.…”