New insight into the molecular mechanisms of MLL-associated leukemia

Zy, Li; Dp, Liu; Cc, Liang

doi:10.1038/sj.leu.2403602

Cited by 49 publications

(35 citation statements)

References 78 publications

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“…MLL, which is the human homolog of the Drosophila trithorax and yeast Set1 proteins, is a histone methyltransferase that is involved in transcriptional regulation in hematopoietic cells [94][95][96][97][98]. Accumulating evidence suggests that the fusion of the MLL protein with other cellular partner proteins alters enzyme function and affects the differentiation of pluripotent hematopoietic stem cells or committed myeloid or lymphoid stem cells by deregulating the expression of the HOX gene [94][95][96]98,99].…”

Section: Topoisomerase II As a Genotoxic Enzymementioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

363

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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Section: Topoisomerase II As a Genotoxic Enzymementioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

363

466

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“…Although MLL is a remarkably promiscuous leukemia-associated gene, current data suggest that these fusion partners fall into two distinct categories: those with a potent transactivation domain and nuclear localization and those that are located in the cytoplasm and possess potential oligomerization motifs (Nakamura et al, 2002;Daser and Rabbitts, 2005;Li et al, 2005). The septins do not possess an activation domain and there is no currently available evidence that they have Figure 3 Detection and analysis of the MLL-SEPT2 genomic breakpoint.…”

Section: Mll-sept2 Fusion Gene In Aml N Cerveira Et Almentioning

confidence: 99%

“…As HOX genes play a key role in the regulation of hematopoietic development, it seems plausible that deregulation of MLL activity might result in abnormal patterns of HOX gene expression in hematopoietic stem cells or progenitors (Daser and Rabbitts, 2005;Li et al, 2005;Slany, 2005). Normally, HOX expression is high in hematopoietic stem cells and becomes gradually extinguished during differentiation (Grier et al, 2005).…”

mentioning

confidence: 99%

“…etoposide and tenoposide) (Pui and Relling, 2000). The presence of an MLL gene abnormality (MLL gene fusion or exon duplication) is associated with poor prognosis in ALL and is an intermediate prognostic factor in AML (Pui and Relling, 2000;Daser and Rabbitts, 2005;Li et al, 2005;Popovic and Zeleznik-Le, 2005;Slany, 2005).…”

mentioning

confidence: 99%

“…The most common MLL fusion partners are AF4 (4q21), AF6 (6q27), AF9 (9p23), AF10 (10p12), ELL (19p13.1) and ENL (19p13.3) (Nakamura et al, 2002;Daser and Rabbitts, 2005). The fusion genes encode chimeric proteins harboring the NH 2 -terminal amino acids of MLL and the COOH-terminal amino acids of the partner protein (Daser and Rabbitts, 2005;Li et al, 2005;Slany, 2005). The major contribution of the fusion partners investigated so far seems to be to convert the rearranged MLL protein to a potent transcriptional activator (Daser and Rabbitts, 2005).…”

mentioning

confidence: 99%

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SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23)

et al. 2006

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We have identified a new mixed lineage leukemia (MLL) gene fusion partner in a patient with treatment-related acute myeloid leukemia (AML) presenting a t(2;11)(q37;q23) as the only cytogenetic abnormality. Fluorescence in situ hybridization demonstrated a rearrangement of the MLL gene and molecular genetic analyses identified a septin family gene, SEPT2, located on chromosome 2q37, as the fusion partner of MLL. RNA and DNA analyses showed the existence of an in-frame fusion of MLL exon 7 with SEPT2 exon 3, with the genomic breakpoints located in intron 7 and 2 of MLL and SEPT2, respectively. Search for DNA sequence motifs revealed the existence of two sequences with 94.4% homology with the topoisomerase II consensus cleavage site in MLL intron 7 and SEPT2 intron 2. SEPT2 is the fifth septin family gene fused with MLL, making this gene family the most frequently involved in MLL-related AML (about 10% of all known fusion partners). The protein encoded by SEPT2 is highly homologous to septins 1, 4 and 5 and is involved in the coordination of several key steps of mitosis. Further studies are warranted to understand why the septin protein family is particularly involved in the pathogenesis of MLL-associated leukemia.

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Identification of a novel fusion gene MLL‐MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23)

Nemoto

Suzukawa

Shimizu

et al. 2007

Genes Chromosomes & Cancer

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We have identified a novel fusion partner of MLL, namely the mastermind like 2 (MAML2 gene), in secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with inv(11)(q21q23). RT-PCR and sequencing revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the NH2-terminal part of MLL and 952 amino acids from the COOH-terminal part of MAML2. The NH2-terminal part of MAML2, a basic domain including a binding site of the intracellular domain of NOTCH, was deleted in MLL-MAML2. MLL-MAML2 in secondary AML/MDS and MECT1-MAML2 in mucoepithelioid carcinoma, benign Wartin's tumor, and clear cell hidradenoma consist of the same COOH-terminal part of MAML2. A luciferase assay revealed that MLL-MAML2 suppressed HES1 promoter activation by the NOTCH1 intracellular domain. MAML2 involving a chimeric gene might contribute to carcinogenesis in multiple neoplasms by the disruption of NOTCH signaling.

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New insight into the molecular mechanisms of MLL-associated leukemia

Cited by 49 publications

References 78 publications

DNA topoisomerase II, genotoxicity, and cancer

DNA topoisomerase II, genotoxicity, and cancer

SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23)

Identification of a novel fusion gene MLL‐MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23)

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