Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16)
- 11 August 2004
- journal article
- research article
- Published by Wiley in Genes, Chromosomes and Cancer
- Vol. 41 (3) , 257-265
- https://doi.org/10.1002/gcc.20077
Abstract
The recurring chromosome translocation t(11;16)(q23;p13) is detected in leukemia patients, virtually all of whom have received previous chemotherapy with topoisomerase (topo) II inhibitors. In the t(11;16), 3′ CBP, on 16p13, is fused to 5′ MLL, on 11q23, resulting in an MLL–CBP fusion gene that plays an important role in leukemogenesis. In this study, we cloned genomic breakpoints of the MLL and CBP genes in the t(11;16) in the SN‐1 cell line and in five patients with therapy‐related leukemia, all of whom had received topo II inhibitors for previous tumors. In all patients except one, both the genomic MLL–CBP and the reciprocal fusions were cloned. Genomic breakpoints in MLL occurred in the 8.3‐kb breakpoint cluster region in all patients, whereas the breakpoints in CBP clustered in an 8.2‐kb region of intron 3 in four patients. Genomic breakpoints in MLL occurred in intron 11 near the topo II cleavage site in the SN‐1 cell line and in one patient, and they were close to LINE repetitive sequences in two other patients. In the remaining two patients, genomic breakpoints were in intron 9 in Alu repeats. Genomic breakpoints in CBP occurred in and around Alu repeats in one and two patients, respectively. In two patients, the breaks were near LINE repetitive sequences, suggesting that repetitive DNA sequences may play a role. No specific recombination motifs were identified at or near the breakpoint junctions. No topo II cleavage sites were detected in introns 2 and 3 of CBP. However, there were deletions and duplications at the breakpoints in both MLL and CBP and microhomologies or nontemplated nucleotides at most of the genomic fusion junctions, suggesting that a nonhomologous end‐joining repair mechanism was involved in the t(11;16).Keywords
This publication has 41 references indexed in Scilit:
- Human Alu element retrotransposition induced by genotoxic stressNature Genetics, 2003
- t(10;16)(q22;p13) and MORF‐CREBBP fusion is a recurrent event in acute myeloid leukemiaGenes, Chromosomes and Cancer, 2003
- Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemiaGenes, Chromosomes and Cancer, 2002
- Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALLOncogene, 2001
- A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cellsOncogene, 1999
- The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB–binding proteinNature Genetics, 1996
- Exon/intron structure of the human ALL‐1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemiasBritish Journal of Haematology, 1996
- BCL2 oncogene translocation is mediated by a chi-like consensus.The Journal of Experimental Medicine, 1992
- The chromosome translocation (11;14)(p13;q11) associated with T cell acute leukemia. Asymmetric diversification of the translocational junctions.The Journal of Experimental Medicine, 1990