Inhibition of growth and induction of apoptosis by all‐
            trans
            retinoic acid in lymphoid cell lines transfected with the PML/RARα fusion gene

Retinoids induce myeloblastic leukemia (HL-60) cells to differentiate into granulocytes, which subsequently die by apoptosis. Retinoid action is mediated through at least two classes of nuclear receptors: retinoic acid receptors, which bind both all-trans retinoic acid and 9-cis retinoic acid, and retinoid X receptors, which bind only 9-cis retinoic acid. Using receptor-selective synthetic retinoids and HL-60 cell sublines with different retinoid responsiveness, we have investigated the contribution that each class of receptors makes to the processes of cellular differentiation and death. Our results demonstrate that ligand activation of retinoic acid receptors is sufficient to induce differentiation, whereas ligand activation of retinoid X receptors is essential for the induction of apoptosis in HL-60 cell lines.

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Response of Aldehyde Dehydrogenase (ALDH) after Cisplatin and All-Trans Retinoic Acid (ATRA) treatment of Spheroid-derived Cells (SDCs) from cervical cancer cell lines

10.1055/s-0038-1671355 ◽

2018 ◽

Cited By ~ 1

Author(s):

J Xu ◽

J Sehouli ◽

AM Kaufmann

Keyword(s):

Cervical Cancer ◽

Retinoic Acid ◽

Cell Lines ◽

Cancer Cell ◽

Aldehyde Dehydrogenase ◽

Cancer Cell Lines ◽

Cervical Cancer Cell ◽

Atra Treatment ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Cancers ◽

10.3390/cancers10110397 ◽

2018 ◽

Vol 10 (11) ◽

pp. 397 ◽

Cited By ~ 11

Author(s):

Krysta Coyle ◽

Cheryl Dean ◽

Margaret Thomas ◽

Dejan Vidovic ◽

Carman Giacomantonio ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Retinoic Acid ◽

Cell Lines ◽

Triple Negative ◽

Atra Treatment ◽

Response Elements ◽

Acid Binding Protein ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

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PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

Cancers ◽

10.3390/cancers12051313 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1313 ◽

Cited By ~ 1

Author(s):

Marta Sobas ◽

Maria Carme Talarn-Forcadell ◽

David Martínez-Cuadrón ◽

Lourdes Escoda ◽

María J. García-Pérez ◽

...

Keyword(s):

Retinoic Acid ◽

Complete Remission ◽

Acute Promyelocytic Leukemia ◽

Fusion Gene ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

High Relapse Rate ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Shed Light

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

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All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

Cell Death and Disease ◽

10.1038/s41419-019-2172-2 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 5

Author(s):

Chi Huu Nguyen ◽

Katharina Bauer ◽

Hubert Hackl ◽

Angela Schlerka ◽

Elisabeth Koller ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Retinoic Acid ◽

Cell Lines ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Dependent Manner ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

AbstractEcotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

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