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PMID: 9238046 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 16 ·1997-08-05 ·Pages 8732-7

Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Doggett NA, Rowley JD, Zeleznik-Le NJ

Abstract

The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.

MeSH Terms
Acute Disease Amino Acid Sequence Antineoplastic Agents/adverse effects,therapeutic use Base Sequence CREB-Binding Protein Chromosomes, Human, Pair 11 Chromosomes, Human, Pair 16 DNA-Binding Proteins/genetics Histone-Lysine N-Methyltransferase Humans Leukemia, Myeloid/drug therapy,genetics Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein Nuclear Proteins/genetics Proto-Oncogenes Trans-Activators Transcription Factors/genetics Translocation, Genetic
Chemicals
Antineoplastic Agents DNA-Binding Proteins KMT2A protein, human Nuclear Proteins Trans-Activators Transcription Factors Myeloid-Lymphoid Leukemia Protein Histone-Lysine N-Methyltransferase CREB-Binding Protein CREBBP protein, human
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sobulo O M
University of Chicago, Department of Medicine, Section of Hematology/Oncology, Chicago, IL 60637-1470, USA.
Borrow J
Tomek R
Reshmi S
Harden A
Schlegelberger B
Housman D
Doggett N A
Rowley J D
Zeleznik-Le N J
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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.94.16.8732
Published
1997-08-05
Pages
8732-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC23102
Subset
IM
Grants
NCI NIH HHS · CA17575 · United States
NCI NIH HHS · CA42557 · United States
NHGRI NIH HHS · HG00299 · United States
Databases
GENBANK
U47741
External Links
PubMed source DOI: 10.1073/pnas.94.16.8732 PMC Full Text View journal details
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