In all age groups and all phenotypes of leukemia, an 11q23 translocation carries a poor prognosis. Previous investigators have reported conflicting results because of the unavailability of specific DNA probesWe have previously used fluorescence in situ hybridization to localize the breakpoint of the common 11q23 translocations to a region of 330 kb. Thus, MLL is one of the oncogenes most frequently involved in hematologic cancers.We identified DNA rearrangements in 61 patients and 3 cell lines with 11q23 abnormalities and delineated an 8.3-kb breakpoint cluster region within the MLL gene by using a 0.74-kb BamHI cDNA fragment as a probe.
The DNA rearrangements are indicated by the arrows. have described a 0.48-kb DdeI genomic fragment that detected rearrangements in a 5.8-kb region in 26 of 30 patients (87 percent) with the (4;11), (9;11), and (11;19) translocationsAlthough the majority of 11q23 translocations involve MLL, molecular studies showed that the 11q23 band contains breakpoints for at least three other cancer-related translocations. MLL is a developmental regulator and is structurally altered in leukemia associated translocations that show an abnormality at band 11q23.
B, location of MLL protein domains in relation to BCR, PTD, and fusion partners. Molecular studies have identified a human homologue of the drosophila trithorax gene (designed HRX or MLL). KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and Transcriptome profiling after deletion of MLL1 in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding.Multiple chromosomal translocations involving this gene are the cause of certain MLL1 has been shown to be an important epigenetic regulator of complex behaviors. ), University of Chicago, Chicago; the Saitama Cancer Center, Saitama, Japan (Y.K. Larson, Le Beau, and Rowley; CA38725 to Dr. Diaz; and CA34775 to Dr. Chaganti), a grant from the Department of Energy (DE-FG02-86ER60408 to Dr. Rowley), a grant from the Spastic Paralysis Research Foundation, Illinois-Eastern Iowa District of Kiwanis International (to Drs.
Chaplin et al. Le Beau is a Scholar of the Leukemia Society of America. ), Molecular Genetics and Cell Biology (H.J.G., S.Z.P., J.D.R.
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(1995) found that all known translocations involving MLL and AF10 or AF17 have involved breakpoints between the zinc finger and leucine zipper domains, and have yielded fusion proteins in which the MLL zinc fingers were replaced with leucine zipper regions. This probe may also have broad clinical application, since all gene rearrangements can be detected with a single probe and a single enzyme digest. The MLL gene has multiple large transcripts in the range of 13 to 15 kb and is transcribed in a centromere-to-telomere ... the specific location of these breakpoints has not been identified. We have identified a single complementary DNA (cDNA) probe from the MLL gene that could detect rearrangements in DNA digested with a single enzyme from all leukemias with the common 11q23 translocations, as well as those with rare chromosomal anomalies with a breakpoint at band 11q23.Samples of bone marrow, lymph nodes, or peripheral blood were obtained at the University of Chicago Medical Center, Saitama Cancer Center, Southwest Biomedical Research Institute, and Memorial Sloan-Kettering Cancer Center. Rearrangements were detected in all the other samples.
Translocations are the most common rearrangements detected, while deletions are rarely seen.