The oncogene<i>EVI1</i>enhances transcriptional and biological responses of human myeloid cells to<i>all-trans</i>retinoic acid

Steinmetz, Birgit; Hackl, Hubert; Slabáková, Eva; Schwarzinger, Ilse; Smějová, Monika; Spittler, Andreas; Arbesú, Itziar; Shehata, Medhat; Souček, Karel; Wieser, Rotraud

doi:10.4161/15384101.2014.946869

Cited by 23 publications

(32 citation statements)

References 87 publications

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“…Altogether, our results suggest that addition of ATRA to the currently used chemotherapy might increase complete remission rates or prevent relapses in EVI-1-positive AML patients. Steinmetz et al have already shown that enhanced expression of EVI-1 in HL60 cells increased the response to ATRA 22 and that the protein GDF15 is part of the ATRA-induced cell cycle block, supporting our results showing that part of the EVI-1-positive AML cases are sensitive to ATRA by inducing differentiation, cell death, and decreased leukemic engraftment.…”

Section: Resultssupporting

confidence: 90%

Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid

Verhagen

Smit

Rutten

et al. 2016

Blood

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Key Points• EVI-1-positive AML cases are sensitive to ATRA.Enhanced expression of ecotropic viral integration site 1 (EVI-1) occurs in ∼10% of acute myeloid leukemia (AML) patients and is associated with a very poor disease outcome.Patients with EVI-1-positive AML have poor initial responses to chemotherapy and high relapse rates, indicating an urgent need for alternative treatment strategies improving clinical outcome for these patients. Because treatment of acute promyelocytic patients with all-trans retinoic acid (ATRA) has improved the survival of these patients substantially, we investigated whether ATRA might also be effective for the subgroup of AML patients with EVI-1 overexpression. Here, we show that a substantial part of the EVI-1-positive AML cases respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts. Most importantly, we demonstrate that in vivo treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Altogether, our results show that a considerable part of the EVI-1-positive primary AML cases are sensitive to ATRA, suggesting that combining ATRA with the currently used conventional chemotherapy might be a promising treatment strategy decreasing relapse rates and enhancing complete remissions in this poor prognostic subgroup of AML patients. (Blood. 2016;127(4):458-463) Introduction Acute myeloid leukemia (AML) is a heterogeneous disease that can be classified based on morphology, immunophenotypic features, and, more importantly, cytogenetic aberrations, molecular abnormalities, gene expression, and methylation signatures.1-3 Aberrant expression of the transcriptional regulator ecotropic viral integration site 1 (EVI-1) occurs in ;10% of human adult AML patients and is associated with particularly aggressive disease and a very poor outcome. Up to 95% of EVI-1-positive patients have an overall survival of ,1 year, 4-6 and novel treatment strategies to improve the survival of AML patients with aberrant expression of EVI-1 are urgently needed. For more than 40 years, most AML patients, including the subgroup with EVI-1 overexpression, have been treated with a combination chemotherapy consisting of cytarabine-arabinoside and an antracycline like daunorubicin. 7,8 Importantly, EVI-1-positive AML cases have an extremely poor initial response to the currently used combination chemotherapy; 39% of EVI-1-positive patients do not achieve complete remission after induction therapy, which is in sharp contrast to the 18% of patients in the other AML subgroups. 5To date, none of other tested alternative regimens have proved to be more effective in AML treatment than the combination of cytarabine and an anthracycline. The exception to this is the treatment of acute promyelocytic (APL) patients with all-trans retinoic acid (ATRA), which increased their survival chances significantly and has turned APL from a poor prognostic leukemia to one that can be cured. 9,10 Because treatment of APL patients with ATRA is very s...

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Section: Resultssupporting

confidence: 90%

Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid

Verhagen

Smit

Rutten

et al. 2016

Blood

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“…Experimental studies suggest EVI1 blocks cellular differentiation by binding to GATA-1 or other specific DNA sequences controlling gene expression, and may be involved in the pathogenesis of some AMLs [7]. EVI1 influences transcription regulation in response to the myeloid differentiation inducing agent, all-trans-retinoic acid (ATRA) [8]. The EVI1 gene is consistently expressed in acute promyelocytic leukemia (APL) cells either constitutively or after ATRA therapy [9].…”

Section: Introductionmentioning

confidence: 99%

“…The EVI1 gene is consistently expressed in acute promyelocytic leukemia (APL) cells either constitutively or after ATRA therapy [9]. ATRA regulates EVI1 expression in blood cells [8].…”

Section: Introductionmentioning

confidence: 99%

“…Several recent studies have shown that ATRA may efficiently drive leukemic cells into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation [19], a FLT3-ITD [20,21], and/or an IDH-1 mutation [22]. Furthermore, it was recently demonstrated that enhanced expression of EVI1 in HL60 cells increased the response to ATRA, that the protein GDF15 is part of the ATRA-induced cell cycle block [8], and that the in vitro part of the EVI1-positive cases are sensitive to ATRA by inducing differentiation and cell death and decreasing leukemic engraftment [23].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1

et al. 2019

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Introduction: EVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment. Methods: In this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1. Results: Seven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool. Conclusion: These primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.

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“…To improve success rates of allogeneic transplantation, we believe new therapeutic approaches should be implemented in AML with high EVI1 expression. In preclinical models, all-trans retinoic acid (ATRA), 8 the CD52 antibody 9 and the BET bromodomain inhibitor JQ1 7,10,11 have shown promising results in EVI1 positive …”

Section: Discussionmentioning

confidence: 99%

A Rare Case of Acute Myeloid Leukemia with a t(2;3) Chromosomal Translocation Characterized by Thrombophilia and Chemoresistance

Bozzetti

Türkmen

Richter

et al. 2016

J Clin Exp Hematopathol

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The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

Cited by 23 publications

References 87 publications

Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid

Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid

Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1

A Rare Case of Acute Myeloid Leukemia with a t(2;3) Chromosomal Translocation Characterized by Thrombophilia and Chemoresistance

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