Role of the Erythropoietin Receptor in ETV6/RUNX1-Positive Acute Lymphoblastic Leukemia

Inthal, Andrea; Krapf, Gerd; Beck, Dominik; Joas, Ruth; Kauer, Max; Orel, Lukas; Fuka, G; Mann, Georg; Panzer-Grümayer, E. Renate

doi:10.1158/1078-0432.ccr-07-5051

Cited by 36 publications

(41 citation statements)

References 43 publications

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“…Prednisolone treatment was performed 11 days after lentiviral transduction and apoptosis assessed by annexin V/propidium iodide staining as reported previously. 30 Information on bioinformatic analysis, pathway analysis targeted by presentation-or relapse-specific CNA, and statistical analysis are provided as supplemental data.…”

Section: Glucocorticoid Treatment and Apoptosis Assaymentioning

confidence: 99%

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

Kuster

Grausenburger

Fuka

et al. 2011

Blood

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101

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Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P ‫؍‬ .01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n ‫؍‬ 3), glucocorticoid receptor NR3C1 (n ‫؍‬ 4), and components of the mismatch repair pathways (n ‫؍‬ 3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/ RUNX1-positive cases demonstrated that BMF deletions were significantly more common in relapse cases (16.6% vs 2.8%; P ‫؍‬ .02). Unlike BMF deletions, which were always already present at diagnosis, NR3C1 and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies. (Blood. 2011;117(9):2658-2667)

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Section: Glucocorticoid Treatment and Apoptosis Assaymentioning

confidence: 99%

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

Kuster

Grausenburger

Fuka

et al. 2011

Blood

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101

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“…20 In accordance with the Declaration of Helsinki, we obtained written informed consent from all patients' parents for using spare leukemia cells in this study. The study was approved by the ethical committees of the Children's Cancer Research Institute and St Anna Kinderspital.…”

Section: Cell Culturementioning

confidence: 99%

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

Fuka

Grausenburger

et al. 2011

Leukemia

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The ETV6/RUNX1 (E/R) gene fusion is generated by the t(12;21) and found in approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia. In contrast to the overwhelming evidence that E/R is critical for the initiation of leukemia, its relevance for the maintenance of overt disease is less clear. To investigate this issue, we suppressed the endogenous E/R fusion protein with lentivirally transduced short hairpin RNA in the leukemia cell lines REH and AT-2, and found a distinct reduction of proliferation and cell survival. In line with the observed concurrent inactivation of the phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway, pharmacological inhibition diminished the phosphorylation of AKT and ribosomal protein S6, and significantly increased the apoptosis rate in E/R-positive leukemias. Moreover, PI3K/mTOR inhibitors sensitized glucocorticoid-resistant REH cells to prednisolone, an observation of potential relevance for improving treatment of drug-resistant relapses. Of note, knockdown of the E/R fusion gene also severely impaired the repopulation capacity of REH cells in non-obese deficient/severe combined immunodeficient mice. Collectively, these data demonstrate that the E/R fusion protein activates the PI3K/AKT/mTOR pathway and is indispensible for disease maintenance. Importantly, these results provide a first rationale and justification for targeting the fusion gene and the PI3K/AKT/mTOR pathway therapeutically.

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“…We and other investigators have also described an increased level of heat shock proteins, survivin, has-mir-125b-2, and erythropoietin receptor in ETV6-RUNX1-positive cells, factors that could provide the survival advantage to the preleukemic clone (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 53%

Cytoskeletal Regulatory Gene Expression and Migratory Properties of B-cell Progenitors Are Affected by the ETV6–RUNX1 Rearrangement

Palmi

Fazio

Savino

et al. 2014

Molecular Cancer Research

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Although the ETV6-RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6-RUNX1-positive cells during this "latency" period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6-RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6-RUNX1-expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6-RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6-RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease.Implications: Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia. Mol Cancer Res; 12(12); 1796-806. Ó2014 AACR. IntroductionETV6-RUNX1, generated by the t(12;21) chromosome translocation, is the most common fusion gene in childhood cancer, selectively associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL; refs. 1-3). The t (12;21) translocation fuses the protein dimerization domain of ETV6 with essentially all of the DNA binding and activating regions of RUNX1, generating an aberrant transcription factor (2, 4). Observations on clinical samples,

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Role of the Erythropoietin Receptor in ETV6/RUNX1-Positive Acute Lymphoblastic Leukemia

Cited by 36 publications

References 43 publications

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

Cytoskeletal Regulatory Gene Expression and Migratory Properties of B-cell Progenitors Are Affected by the ETV6–RUNX1 Rearrangement

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