MLL fusions: Pathways to leukemia

Liu, Han; Cheng, Emily H.; Hsieh, James J.

doi:10.4161/cbt.8.13.8924

Cited by 94 publications

(88 citation statements)

References 119 publications

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“…In addition to deletions, translocations have also been identified. The most frequent translocations occur within leukemia's, which exhibit a multitude of MLL gene fusion products generated by a variety of chromosomal translocations (Liu et al, 2009). Neuroblastomas are pediatric tumors that arise from neuroblasts of the sympathetic nervous system.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma

et al. 2011

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Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization and single-nucleotide polymorphism arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box R1 transcription factor (FOXR1). Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of fork-head box factormediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in overexpression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma.

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Section: Introductionmentioning

confidence: 99%

Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma

et al. 2011

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“…1). More than 60 different MLL fusion partners have been identified (2,3). MLL fusion proteins confer an unusual ability to transform hematopoietic cells into leukemic stem cells (LSC; refs.…”

Section: Introductionmentioning

confidence: 99%

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Bousquet

Zhuang

et al. 2013

Molecular Cancer Research

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The microRNA miR-150, a critical regulator of hematopoiesis, is downregulated in mixed-lineage leukemia (MLL). In this study, miR-150 acts as a potent leukemic tumor suppressor by blocking the oncogenic properties of leukemic cells. By using MLL-AF9-transformed cells, we demonstrate that ectopic expression of miR-150 inhibits blast colony formation, cell growth, and increases apoptosis in vitro. More importantly, ectopic expression of miR-150 in MLL-AF9-transformed cells completely blocked the development of myeloid leukemia in transplanted mice. Furthermore, gene expression profiling revealed that miR-150 altered the expression levels of more than 30 "stem cell signature" genes and many others that are involved in critical cancer pathways. In addition to the known miR-150 target Myb, we also identified Cbl and Egr2 as bona fide targets and shRNA-mediated suppression of these genes recapitulated the pro-apoptotic effects observed in leukemic cells with miR-150 ectopic expression.In conclusion, we demonstrate that miR-150 is a potent leukemic tumor suppressor that regulates multiple oncogenes.Implications: These data establish new, key players for the development of therapeutic strategies to treat MLL-AF9-related leukemia. Mol Cancer Res; 11(8); 912-22. Ó2013 AACR.

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“…The t(4;11)(q21;q23) is the second most popular chromosomal translocation in adults with ALL. However, the detailed role of this fusion protein in leukemogenesis is not well understood (Erfurth et al, 2008;Liu et al, 2009). All MLL fusion proteins retain the amino-terminal portion containing AT hooks and the MLL CxxC domain, thus preserving DNA-binding activity.…”

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confidence: 99%

“…Chromosomal translocations fuse the amino-terminal end of MLL in-frame to one of more than 50 partner proteins, and different translocations can result in different prognosis (Liu et al, 2009). Of these MLL-associated leukemias, MLL-AF4 acute lymphocytic leukemia (ALL), which results from a balanced translocation between MLL and AF4 (t(4;11)(q21;q23)), occurs in B50, 2 and 5-6% of infant, child and adult ALL cases, respectively.…”

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confidence: 99%

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

Dou

Zheng

et al. 2011

Oncogene

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Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL-AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL-AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3 0 untranslated regions may modulate MLL-AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL-AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL-AF4 expression in MLL-AF4 ALL samples. Restoration of miR-143 in MLL-AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL-AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL-AF4-negative primary blasts, which was directly associated with expression of the MLL-AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL-AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL-AF4 B-cell ALL.

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MLL fusions: Pathways to leukemia

Cited by 94 publications

References 119 publications

Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma

Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

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