Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias

Tkachuk, Denis; Köhler, Sabine; Cleary, Michael L.

doi:10.1016/0092-8674(92)90602-9

Cited by 865 publications

(657 citation statements)

References 32 publications

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“…The analysis of chromosomal translocations a ecting chromosome 11 at band q23 in leukaemias has shown that these events involve fusions between the human trithorax (MLL) gene (Djabali et al, 1992;Gu et al, 1992;Tkachuk et al, 1992;Ziemin-van der Poel et al, 1991) and a variety of partner genes each providing a COOH region to the resultant fusion protein. These translocations result in in-frame fusions suggesting an important role for the di erent COOH regions in the oncogenic transformation.…”

Section: Introductionmentioning

confidence: 99%

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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The MLL gene is reciprocally translocated with one of a number of di erent partner genes in a proportion of human acute leukaemias. The precise mechanism of oncogenic transformation is unclear since most of the partner genes encode unrelated proteins. However, two partner genes, AF10 and AF17 are related through the presence of a cysteine rich region and a leucine zipper. The identi®cation of other proteins with these structures will aid our understanding of their role in normal and leukaemic cells. We report the cloning of a novel human gene (BRL) which encodes a protein containing a cysteine rich region related to that of AF10 and AF17 and is overall most closely related to the previously known protein BR140. BRL maps to chromosome 22q13 and shows high levels of expression in testis and several cell lines. The deduced protein sequence also contains a bromodomain, four potential LXXLL motifs and four predicted nuclear localization signals. A monoclonal antibody raised to a BRL peptide sequence con®rmed its widespread expression as a 120 Kd protein and demonstrated localization to the nucleus within spermatocytes.

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Section: Introductionmentioning

confidence: 99%

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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“…The usual consequence of 11q23 translocation is the fusion of Nterminal sequences of the MLL gene to a wide variety of partners producing chimeric products with putative transforming activities. 13,14 Cases of childhood acute leukemia with rearrangements of this gene are generally characterized by young age, high white blood cell (WBC) count, organomegaly, central nervous system involvement, and poor prognosis. 15 The lineage of leukemia with MLL gene rearrangements varies according to its type of translocation.…”

Section: Introductionmentioning

confidence: 99%

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

et al. 1997

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p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 × 10 9 /l vs 271 × 10 9 /l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.

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“…On a molecular level these events a ect the MLL gene that spans the common breakpoint at 11q23. MLL (also called HRX, ALL-1, Htrx) codes for a large 3968 amino acid protein that shows limited but signi®cant homology to the Drosophila trithorax protein TRX (Ziemin van der Poel et al, 1991;Djabali et al, 1992;Gu et al, 1992;Tkachuk et al, 1992). Trx is a member of the trithorax group (TRX-G) of activator genes that counteracts the polycomb group (PC-G) of repressors and it is required to maintain, but not to initiate, the expression of the Hom-C homeotic genes during Drosophila development (Eissenberg et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Two DNA binding motifs, the socalled AT-hooks and a domain with homology to eukaryotic methyltransferases (MT), have been identi®ed in the N-terminal portion of MLL. Further downstream the protein contains three tandem LAP/ PHD zinc ®nger motifs and a C-terminal SET domain that is characteristic for proteins involved in chromatin structure rearrangements (Tkachuk et al, 1992). The translocations fuse the N-terminal portion of MLL including the AT-hooks and the MT-motif to a large group of heterogeneous partner proteins.…”

Section: Introductionmentioning

confidence: 99%

ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1 (ABI1) that is fused to MLL in t(10;11)+

et al. 2000

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Translocations of the chromosomal locus 11q23 that disrupt the MLL gene (alternatively ALL-1 or HRX) are frequently found in children's leukemias. These events fuse the MLL amino terminus in frame with a variety of unrelated proteins. Up to date, 16 di erent fusion partners have been characterized and more are likely to exist. No general unifying property could yet be detected amongst these proteins. We show here that the frequent MLL fusion partner ENL at 19p13.1 interacts with the human homologue of the mouse Abl-Interactor 1 (ABI1) protein. ABI1 in turn, is fused to MLL in the t(10;11)(p11.2;q23) translocation. ABI1 was identi®ed as an ENL binding protein by a yeast two-hybrid screen. The interaction of ENL and ABI1 could be veri®ed in vitro by far-Western blot assays and GST-pulldown studies as well as in vivo by co-immunoprecipitation experiments. A structure-function analysis identi®ed an internal region of ENL and a composite motif of ABI1 including an SH3 domain as mutual binding partners. These data introduce novel aspects that might contribute to the understanding of the process of leukemogenesis by MLL fusion proteins.

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Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias

Cited by 865 publications

References 32 publications

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1 (ABI1) that is fused to MLL in t(10;11)+

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