Acute myeloid leukemia induced by MLL-ENL is cured by oncogene ablation despite acquisition of complex genetic abnormalities

Horton, Sarah J.; Walf-Vorderwülbecke, Vanessa; Chatters, Steve; Sebire, Neil J.; Boer, Jasper de; Williams, Owen

doi:10.1182/blood-2008-07-170480

Cited by 25 publications

(32 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Secondary mutations will have to occur to convert this smoldering state into an acute leukemia. Such mutations have been found in murine experimental models 111 and also in patient cells that frequently carry an activating mutation in the receptor tyrosine kinase Flt-3. 112,113 In a very surprising development, it has also recently been suggested that increased glycogen-synthase-kinase 3 activity is involved in the etiology of mixed lineage leukemia, an unexpected finding because GSK3 normally is a tumor suppressor gene.…”

Section: Mll Fusion Downstream Targets and The Problem Of Pediatric Lmentioning

confidence: 99%

The molecular biology of mixed lineage leukemia

Slany¹

2009

Haematologica

285

280

View full text Add to dashboard Cite

Mixed lineage leukemia is a very aggressive blood cancer that predominantly occurs in pediatric patients. In contrast to other types of childhood acute leukemias, mixed lineage leukemia presents with a dismal prognosis and despite the availability of advanced treatment methods cure rates have stagnated over the last years. Mixed lineage leukemia is characterized by the presence of MLL fusion proteins that are the result of chromosomal translocations affecting the MLL gene at 11q23. These events juxtapose the amino-terminus of the histone methyltransferase MLL with a variety of different fusion partners that destroy normal histone methyltransferase function of MLL and replace it by heterologous functions contributed by the fusion partner. The resulting chimeras are transcriptional regulators that take control of targets normally controlled by MLL with the clustered HOX homeobox genes as prominent examples. Recent studies suggested that MLL fusion partners activate transcription by two different mechanisms. Some of these proteins are themselves chromatin modifiers that introduce histone acetylation whereas other fusion partners can recruit histone methyltransferases.In particular, histone H3 specific methylation at lysine 79 catalyzed by DOT1L has been recognized as a hallmark of chromatin activated by MLL fusion proteins. Interestingly, several frequent MLL fusion partners seem to coordinate DOT1L activity with a protein complex that stimulates the elongation phase of transcription by phosphorylating the carboxy-terminal repeat domain of RNA polymerase II. The discovery of these novel enzymatic activities that are essentially involved in MLL fusion protein function presents potential new targets for a rational drug development.

show abstract

Section: Mll Fusion Downstream Targets and The Problem Of Pediatric Lmentioning

confidence: 99%

The molecular biology of mixed lineage leukemia

Slany¹

2009

Haematologica

285

280

View full text Add to dashboard Cite

show abstract

“…The clonal character as well as a latency period of 60 to 4200 days of the induced leukemia suggested that although MLL-X fusions are essential, they might not be fully sufficient for inducing a leukemic phenotype in vivo. [15][16][17][18][19] Elevated MN1 expression was not only associated with the presence of distinct genetic alterations (e.g. inv16, alterations of the EVI1 gene locus) in human leukemia, but the MN1 gene locus was also target of proviral integration site in mouse leukemia models induced by bone marrow reconstitution of retrovirally expressed oncogenes, such as mutant AML1 or NUP98-HOXD13.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia

et al. 2010

View full text Add to dashboard Cite

Retroviral expression of leukemogenic oncogenes in the murine hematopoietic system is essential but not sufficient to induce acute leukemia. Proviral integration-mediated elevated expression of the meningioma 1 (MN1) oncogene suggested MN1 acting as cooperating event in mixed-lineage leukemia 1 (MLL) and eleven nineteen leukemia (ENL)-induced murine leukemia. Indeed, co-expression of MN1 with MLL-ENL enhanced transformation in vivo, and resulted in a significantly reduced latency for induction of an aggressive acute leukemia when compared with MN1 or MLL-ENL alone. In addition, coexpression of MN1 increased the granulocyte macrophage progenitor cell population with leukemia-initiating properties as shown in secondary transplantation experiments. Gene expression profiling experiments identified putative downstream MN1 targets, of which FMS-like tyrosine kinase 3 (FLT3) and CD34 were upregulated in both MN1-overexpressing murine leukemias and in pediatric acute leukemias with high MN1 levels. Interestingly, small interfering RNA (siRNA)-mediated MN1 knockdown resulted in cell cycle arrest and impaired clonogenic growth of human leukemia cell lines with high MN1 levels. Our work shows for the first time that high MN1 levels are important for the growth of leukemic cells, and that increased MN1 expression can synergize with MLL-ENL and probably other transforming fusion genes in leukemia induction through a distinct gene expression program that is able to expand the leukemia-initiating cell population.

show abstract

“…76 However, due to the heterogeneity of the LSC compartment, the best potential target would be one Therapies that target both LSCs and the bulk population would be ideal but may not be practical because of the critical differences between these populations. At the same time, off-target effects that result in toxicity to HSCs may not be acceptable.…”

Section: Targeting Leukemia Stem Cellsmentioning

confidence: 99%