The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene

Gu, Yansong; Nakamura, Tatsuya; Alder, Hansjüerg; Prasad, R; Canaani, Ora; Cimino, Giuseppe; Croce, Carlo M.; Canaani, Eli

doi:10.1016/0092-8674(92)90603-a

Cited by 806 publications

(581 citation statements)

References 26 publications

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“…This locus shows homology to sequences within the Drosophila 'trithorax' gene, a developmental regulator. 7,8 As these aberrations were found in AML as well as acute lymphoblastic leukemia (ALL), the gene was called mixedlineage leukemia. 9 Recent studies show that the MLL group itself is genetically and clinically heterogeneous, as more than 60 different translocation partners of the MLL gene with differences in outcome have been described to date.…”

Section: Introductionmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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Section: Introductionmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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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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“…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%

“…Sixteen fusion partners have been already isolated and sequenced. These include AF4 (4q21), AF9 (9p22), ENL (19p13.3), ELL (19p13.1), EEN (19p13), AF6 (6q27), EPS15 (1p32), AFX (Xq13), AF10 (10p12), AF17 (17q21), CBP (16p13), MSF (17q25), p300 (22q13), AF6q21 (6q21), ABI1 (10p12), and hCDCrel (22q11.2) (Gu et al, 1992;Nakamura et al, 1993;Rubnitz et al, 1994;Thirman et al, 1994;So et al, 1997;Prasad et al, 1993Prasad et al, , 1994Bernard et al, 1994;Parry et al, 1994;Chaplin et al, 1995;Sobulo et al, 1997;Osaka et al, 1999;Ida et al, 1997;Hillion et al, 1997;Taki et al, 1998;Megonigal et al, 1998). The large number of seemingly unrelated fusion partners initially gave rise to the speculation that the fusion of MLL itself is the essential event leading to leukemia by a loss of function mechanism.…”

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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The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene

Cited by 806 publications

References 26 publications

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

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

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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