Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT

Geßner, Andreas; Thomas, Maria; Castro, P Garrido; Büchler, Lorina; Scholz, Anja; Brümmendorf, Tim H.; Soria, N Martinez; Vormoor, Josef; Greil, Johann; Heidenreich, Olaf

doi:10.1038/leu.2010.155

Cited by 39 publications

(37 citation statements)

References 60 publications

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“…44 Recent experiments in human cells have also linked transformation by MLL-fusions to increased telomerase activity. 29,45 Thus, immortalization of human cord blood-derived HPC by MLL-AF9 was accompanied by reactivation of telomerase, 29 while knock down of MLL-AF4 in human acute lymphoblastic leukemia cell lines resulted in decreased telomerase activity. 45 Furthermore, in addition to transcriptional regulation of TERT, RUVBL2, together with RUVBL1, was shown to be essential for temolerase holoenzyme assembly.…”

Section: Discussionmentioning

confidence: 99%

“…29,45 Thus, immortalization of human cord blood-derived HPC by MLL-AF9 was accompanied by reactivation of telomerase, 29 while knock down of MLL-AF4 in human acute lymphoblastic leukemia cell lines resulted in decreased telomerase activity. 45 Furthermore, in addition to transcriptional regulation of TERT, RUVBL2, together with RUVBL1, was shown to be essential for temolerase holoenzyme assembly. 27 Our data are consistent with RUVBL2 regulating telomerase activity in human MLL-AF9 leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

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The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis

Osaki¹,

Walf-Vorderwülbecke²,

Mangolini³

et al. 2013

Leukemia

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The most frequent chromosomal translocations in pediatric acute myeloid leukemia affect the 11q23 locus and give rise to mixed lineage leukemia (MLL) fusion genes, MLL-AF9 being the most prevalent. The MLL-AF9 fusion gene has been shown to induce leukemia in both mouse and human models. In this study, we demonstrate that leukemogenic activity of MLL-AF9 requires RUVBL2 (RuvB-like 2), an AAA þ ATPase family member that functions in a wide range of cellular processes, including chromatin remodeling and transcriptional regulation. Expression of RUVBL2 was dependent on MLL-AF9, as it increased upon immortalization of human cord blood-derived hematopoietic progenitor cells with the fusion gene and decreased following loss of fusion gene expression in conditionally immortalized mouse cells. Short hairpin RNA-mediated silencing experiments demonstrated that both the immortalized human cells and the MLL-AF9-expressing human leukemia cell line THP-1 required RUVBL2 expression for proliferation and survival. Furthermore, inhibition of RUVBL2 expression in THP-1 cells led to reduced telomerase activity and clonogenic potential. These data were confirmed with a dominant-negative Walker B-mutated RUVBL2 construct. Taken together, these data suggest the possibility of targeting RUVBL2 as a potential therapeutic strategy for MLL-AF9-associated leukemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis

Osaki¹,

Walf-Vorderwülbecke²,

Mangolini³

et al. 2013

Leukemia

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show abstract

“…33,34 An additional gene localized to 5p15.33 that may be affected by abnormal IRX2 expression is TERT that maintains genomic integrity by regulating telomerase activity to allow restoration of telomere length. 35 Maintaining TERT expression and preventing senescence may be a mechanism whereby fusion proteins, such as MLL-AFF1, mediated by HOXA genes, support self-renewal in leukemic cells. 36 Unsupervised hierarchical clustering of the MLL-AFF1 infants in our cohort yielded 2 cluster groups with distinct gene expression signatures dominated by homeobox genes (HOXA or IRX).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

Kang

Wilson

Harvey

et al. 2012

Blood

123

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Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of eventfree survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n ‫؍‬ 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups. (Blood. 2012; 119(8):1872-1881)

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“…LSCs possess limitless self-renewal that is engendered by oncogenic activation of numerous pathways including the HoxA cluster (Krivtsov et al, 2006), Wnt-beta catenin (Heidel et al, 2012; Wang et al, 2010), or through telomerase activation (Gessner et al, 2010). The telomerase holoenzyme consists of a reverse transcriptase subunit (TERT), an RNA template subunit (TERC), and a protective shelterin scaffold.…”

Section: Introductionmentioning

confidence: 99%

Telomerase Inhibition Effectively Targets Mouse and Human AML Stem Cells and Delays Relapse following Chemotherapy

et al. 2014

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SUMMARY Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc−/− LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Together, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs.

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Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT

Cited by 39 publications

References 60 publications

The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis

The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

Telomerase Inhibition Effectively Targets Mouse and Human AML Stem Cells and Delays Relapse following Chemotherapy

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