The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

Caslini, Corrado; Alarcòn, ASerna; Hess, JL; Tanaka, Ryuhei; Murti, K.G.; Biondi, Andrea

doi:10.1038/sj.leu.2401933

Cited by 44 publications

(49 citation statements)

References 62 publications

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“…This pattern has been reported by others using anti-AF4 antibodies. 36 This murine AF4 expression was always limited to the nucleus and was never cytoplasmic. This was in contrast to EGFP expression, which was seen in both the cytoplasm and nucleus, and appeared diffuse (Figure 2b).…”

Section: Control Of Af4 Subcellular Localizationmentioning

confidence: 93%

“…The FLAG-MLL-AF4 construct was a kind gift of Masao Seto. Both the FLAG-MLL and FLAG-MLL-AF4 constructs were previously used by Hess et al 36 Inserts were generated either by PCR with high-fidelity Pfu polymerase, or by enzymatic excision from other plasmids. PCR inserts were sequenced to ensure proper orientation and correct sequence.…”

Section: Plasmid Constructionmentioning

confidence: 99%

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MLL fusion partners AF4 and AF9 interact at subnuclear foci

et al. 2003

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The MLL gene is involved in translocations associated with both acute lymphoblastic and acute myelogenous leukemia. These translocations fuse MLL with one of over 30 partner genes. Collectively, the MLL partner genes do not share a common structural motif or biochemical function. We have identified a protein interaction between the two most common MLL fusion partners AF4 and AF9. This interaction is restricted to discrete nuclear foci we have named 'AF4 bodies'. The AF4 body is non-nucleolar and is not coincident with any known nuclear structures we have examined. The AF4-AF9 interaction is maintained by the MLL-AF4 fusion protein, and expression of the MLL-AF4 fusion can alter the subnuclear localization of AF9. In view of other research indicating that other MLL fusion partners also interact with one another, these results suggest that MLL fusion partners may participate in a web of protein interactions with a common functional goal. The disruption of this web of interactions by fusion with MLL may be important to leukemogenesis.

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Section: Control Of Af4 Subcellular Localizationmentioning

confidence: 93%

Section: Plasmid Constructionmentioning

confidence: 99%

MLL fusion partners AF4 and AF9 interact at subnuclear foci

et al. 2003

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“…We therefore hypothesized that other MLL chimeras might also rely on partner proteins for their association with p53. To facilitate the analysis of leukemic fusion binding to p53 in vivo, we generated an internal deletion in the MLL N terminus to eliminate specific sequences that mediate the strong association of MLL with chromatin and the nuclear matrix (8,9), which makes conventional binding assays nearly impossible (data not shown). Immunoprecipitation/Western blot analysis revealed that MLL fusion mutants strongly bound to p53 in vivo, thus indicating that intact partner proteins are sufficient for the association of MLL chimeras with p53 (Fig.…”

Section: Mll Fusions Suppress Transcriptional Activity Of Exogenous P53-mentioning

confidence: 99%

Multiple Mixed Lineage Leukemia (MLL) Fusion Proteins Suppress p53-mediated Response to DNA Damage

Wiederschain

Kawai

Shilatifard

et al. 2005

Journal of Biological Chemistry

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Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are often observed in acute leukemias of both myeloid and lymphocytic origin. Expression of MLL fusion proteins is known to induce malignant transformation of normal blood progenitors; however, molecular mechanisms of this process are still poorly understood. In this study we investigated the effect of several frequently detected MLL fusion proteins on p53 transcriptional activity. Our data show that MLL-AF9, MLL-AF10, MLL-ENL, and MLL-ELL substantially down-regulate p53-mediated induction of p21, MDM2, and Bax in response to DNA damage. Furthermore, we identify the reduction in p53 acetylation by p300 as a major mechanism of the inhibitory effect of MLL leukemic fusions. Our data suggest that abrogation of p53 functional activity can be a common feature of MLL fusion-mediated leukemogenesis.Reciprocal chromosomal rearrangements involving the mixed lineage leukemia (MLL) 1 gene at the 11q23 locus are frequently detected in patients diagnosed with acute forms of both myeloid and lymphocytic leukemias (1, 2). As a result of these chromosomal aberrations, the N terminus of MLL is consistently fused in-frame to a number of partner proteins. Although more than 30 genes have been identified as fused to MLL in human leukemias, AF4, AF9, ENL, AF10, and ELL account for the absolute majority of recurrent MLL partners (3). The precise molecular mechanisms underlying the oncogenic function of MLL fusions are still poorly understood. We and others have recently shown that transient expression of MLL-ELL results in a potent and specific inhibition of p53 (4, 5), a critical tumor suppressor protein that mediates expression of multiple cell cycle regulatory and pro-apoptotic genes in response to stress (6). The disruption of p53 interactions with its co-activator p300 has been demonstrated to contribute to the MLL-ELL inhibitory effect on p53 (5).In the present study, we systematically analyzed the effect of additional frequently detected MLL fusion proteins on p53 activity. Our results show that MLL-AF9, MLL-AF10, and MLL-ENL associate with p53 through their partner proteins and significantly down-regulate the transcriptional activity of p53 in reporter assays. Furthermore, stable cell lines expressing low levels of MLL-AF9, MLL-AF10, MLL-ENL, and MLL-ELL exhibit impaired endogenous p53 response to both ionizing radiation and adriamycin treatment. Although having no discernible effect on p53 protein levels, MLL fusions significantly suppress p53-mediated induction of p21, MDM2, and Bax in response to various types of DNA damage. We also find that MLL fusions inhibit stress-induced p300-mediated p53 acetylation, which could explain their inhibitory effect on p53. Collectively, our data identify p53 functional inactivation as a common characteristic of multiple MLL fusions. EXPERIMENTAL PROCEDURESPlasmid Design-pcDNA-FLAG-p53, Myc-p53, pcDNA-FLAG-p53(6KR), pcDNA-MLL-ELL and pcDNA-MLL-ELL⌬CT have been described previously (5). MLL-AF9, MLL-AF10, and MLL-EN...

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“…Infant pro-B acute lymphoblastic leukemia (ALL) harboring the fusion MLL-AF4 is characterized by a very brief latency and dismal prognosis, raising the question of how this infant cancer evolves so quickly [2,3]. Moreover, the exceptionally high concordance rate of this leukemia in monozygotic twin infants, approaching 100% [4], suggests that all the necessary genetic events required for leukemogenesis are accomplished prenatally [5].…”

Section: Introductionmentioning

confidence: 99%

A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

Bueno¹,

Montes²,

Melén³

et al. 2012

Cell Res

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The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well established that MLL-AF4 arises prenatally during human development, its effects on hematopoietic development in utero remain unexplored. We have created a human-specific cellular system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Functional studies, clonal analysis and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. MLL-AF4 acts as a global transcriptional activator and a positive regulator of homeobox gene expression in hESCs. Functionally, MLL-AF4 enhances the specification of hemogenic precursors from hESCs but strongly impairs further hematopoietic commitment in favor of an endothelial cell fate. MLL-AF4 hESCs are transcriptionally primed to differentiate towards hemogenic precursors prone to endothelial maturation, as reflected by the marked upregulation of master genes associated to vascular-endothelial functions and early hematopoiesis. Furthermore, we report that MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells. This work illustrates how hESCs may provide unique insights into human development and further our understanding of how leukemic fusion genes, known to arise prenatally, regulate human embryonic hematopoietic specification.

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The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

Cited by 44 publications

References 62 publications

MLL fusion partners AF4 and AF9 interact at subnuclear foci

MLL fusion partners AF4 and AF9 interact at subnuclear foci

Multiple Mixed Lineage Leukemia (MLL) Fusion Proteins Suppress p53-mediated Response to DNA Damage

A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

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