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

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

^*University of Chicago, Department of Medicine, Section of Hematology/Oncology, Chicago, IL 60637-1470; ^†Massachusetts Institute of Technology, Center for Cancer Research, Cambridge, MA 02139; ^‡University of Kiel, Department of Human Genetics, Kiel, 24105 Germany; and ^§Los Alamos National Laboratory, Life Sciences Division and Center for Human Genome Studies, Los Alamos, NM, 87545

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.

Footnotes

Janet D. Rowley
Data deposition: The human CBP sequence reported on in this paper has been deposited in the GenBank database (accession no. U47741).
ABBREVIATIONS:

CREB,

cAMP-response element binding protein;

CBP,

CREB binding protein;

RTS,

Rubinstein–Taybi syndrome;

UTR,

untranslated region;

PHD,

plant homeodomain;

PAC,

p1 artificial chromosome;

YAC,

yeast artificial chromosome;

FISH,

fluorescence in situ hybridization;

STS,

sequence-tagged site;

BCR,

breakpoint cluster region