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PMID: 9600980 Published · ppublish English Case Reports Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 11 ·1998-05-26 ·Pages 6413-8

Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML, Felix CA

Abstract

We examined the MLL genomic translocation breakpoint in acute myeloid leukemia of infant twins. Southern blot analysis in both cases showed two identical MLL gene rearrangements indicating chromosomal translocation. The rearrangements were detectable in the second twin before signs of clinical disease and the intensity relative to the normal fragment indicated that the translocation was not constitutional. Fluorescence in situ hybridization with an MLL-specific probe and karyotype analyses suggested t(11;22)(q23;q11. 2) disrupting MLL. Known 5' sequence from MLL but unknown 3' sequence from chromosome band 22q11.2 formed the breakpoint junction on the der(11) chromosome. We used panhandle variant PCR to clone the translocation breakpoint. By ligating a single-stranded oligonucleotide that was homologous to known 5' MLL genomic sequence to the 5' ends of BamHI-digested DNA through a bridging oligonucleotide, we formed the stem-loop template for panhandle variant PCR which yielded products of 3.9 kb. The MLL genomic breakpoint was in intron 7. The sequence of the partner DNA from band 22q11.2 was identical to the hCDCrel (human cell division cycle related) gene that maps to the region commonly deleted in DiGeorge and velocardiofacial syndromes. Both MLL and hCDCrel contained homologous CT, TTTGTG, and GAA sequences within a few base pairs of their respective breakpoints, which may have been important in uniting these two genes by translocation. Reverse transcriptase-PCR amplified an in-frame fusion of MLL exon 7 to hCDCrel exon 3, indicating that an MLL-hCDCrel chimeric mRNA had been transcribed. Panhandle variant PCR is a powerful strategy for cloning translocation breakpoints where the partner gene is undetermined. This application of the method identified a region of chromosome band 22q11.2 involved in both leukemia and a constitutional disorder.

MeSH Terms
Abnormalities, Multiple/genetics Acute Disease Base Sequence Cell Cycle Proteins/genetics Chromosomes, Human, Pair 11 Chromosomes, Human, Pair 22 DNA-Binding Proteins/genetics DiGeorge Syndrome/genetics Diseases in Twins Face/abnormalities Gene Deletion Genome, Human Heart Defects, Congenital/genetics Histone-Lysine N-Methyltransferase Humans Infant Leukemia, Myeloid/genetics Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein Proto-Oncogenes Syndrome Transcription Factors Translocation, Genetic Twins
Chemicals
Cell Cycle Proteins DNA-Binding Proteins KMT2A protein, human Transcription Factors Myeloid-Lymphoid Leukemia Protein Histone-Lysine N-Methyltransferase
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Megonigal M D
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Rappaport E F
Jones D H
Williams T M
Lovett B D
Kelly K M
Lerou P H
Moulton T
Budarf M L
Felix C A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.11.6413
Published
1998-05-26
Pages
6413-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC27754
Subset
IM
Grants
NIDCD NIH HHS · P01 DC002027 · United States
NCI NIH HHS · 1R29CA66140-03 · United States
NIDCD NIH HHS · DC02027 · United States
NHLBI NIH HHS · HL51533 · United States
Databases
GENBANK
AF061152, AF061153, AF061154
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1073/pnas.95.11.6413 PMC Full Text View journal details
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