Evi1 Counteracts Anti-Leukemic and Stem Cell Inhibitory Effects of All-Trans Retinoic Acid on Flt3-ITD/Npm1c-Driven Acute Myeloid Leukemia Cells

All-trans retinoic acid (atRA) has a dramatic impact on the survival of patients with acute promyelocytic leukemia, but its therapeutic value in other types of acute myeloid leukemia (AML) has so far remained unclear. Given that AML is a stem cell-driven disease, recent studies have addressed the effects of atRA on leukemic stem cells (LSCs). atRA promoted stemness of MLL-AF9-driven AML in an Evi1-dependent manner but had the opposite effect in Flt3-ITD/Nup98-Hoxd13-driven AML. Overexpression of the stem cell-associated transcription factor EVI1 predicts a poor prognosis in AML, and is observed in different genetic subtypes, including cytogenetically normal AML. Here, we therefore investigated the effects of Evi1 in a mouse model for cytogenetically normal AML, which rests on the combined activity of Flt3-ITD and Npm1c mutations. Experimental expression of Evi1 on this background strongly promoted disease aggressiveness. atRA inhibited leukemia cell viability and stem cell-related properties, and these effects were counteracted by overexpression of Evi1. These data further underscore the complexity of the responsiveness of AML LSCs to atRA and point out the need for additional investigations which may lay a foundation for a precision medicine-based use of retinoids in AML.

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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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Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

Pharmaceuticals ◽

10.3390/ph14050423 ◽

2021 ◽

Vol 14 (5) ◽

pp. 423

Author(s):

Øystein Bruserud ◽

Galina Tsykunova ◽

Maria Hernandez-Valladares ◽

Hakon Reikvam ◽

Tor Henrik Anderson Tvedt

Keyword(s):

Valproic Acid ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Low Intensity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Low Toxicity ◽

Acute Myeloid

Even though allogeneic stem cell transplantation is the most intensive treatment for acute myeloid leukemia (AML), chemo-resistant leukemia relapse is still one of the most common causes of death for these patients, as is transplant-related mortality, i.e., graft versus host disease, infections, and organ damage. These relapse patients are not always candidates for additional intensive therapy or re-transplantation, and many of them have decreased quality of life and shortened expected survival. The efficiency of azacitidine for treatment of posttransplant AML relapse has been documented in several clinical trials. Valproic acid is an antiepileptic fatty acid that exerts antileukemic activity through histone deacetylase inhibition. The combination of valproic acid and all-trans retinoic acid (ATRA) is well tolerated even by unfit or elderly AML patients, and low-toxicity chemotherapy (e.g., azacitidine) can be added to this combination. The triple combination of azacitidine, valproic acid, and ATRA may therefore represent a low-intensity and low-toxicity alternative for these patients. In the present review, we review and discuss the general experience with valproic acid/ATRA in AML therapy and we discuss its possible use in low-intensity/toxicity treatment of post-allotransplant AML relapse. Our discussion is further illustrated by four case reports where combined treatments with sequential azacitidine/hydroxyurea, valproic acid, and ATRA were used.

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Bexarotene derivatives modify responses in acute myeloid leukemia

10.1101/2021.05.17.444475 ◽

2021 ◽

Author(s):

Gayla Hadwiger ◽

Orsola di Martino ◽

Margaret Ashley Ferris ◽

Anh Vu ◽

Thomas E. Frederick ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Leukemia Cell ◽

Promyelocytic Leukemia ◽

Leukemia Cell Line ◽

Structure Activity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

The retinoids all-trans retinoic acid (ATRA) and bexarotene are active in acute myeloid leukemia (AML), but responses beyond acute promyelocytic leukemia (APL) have been more modest than APL responses. To determine whether chemical modification of bexarotene might augment retinoid responses in AML, we screened a series of 38 bexarotene derivatives for activity in a mouse MLL-AF9 leukemia cell line, which exhibits strong synergistic sensitivity to the combination of ATRA and bexarotene. We found that RXRA potency correlated with anti-leukemic activity and that only one compound (103-4) with dual RARA/RXRA activity was capable of ATRA-independent anti-leukemic activity. We evaluated bioisostere and cyclohexane modifications for potential resistance to P450 metabolism and found that bioisosteres reduced potency and that bezopyran, cyclopentane, and cyclohexene modifications only modestly reduced susceptibility to metabolism. Collectively, these studies provide a map of the structure-activity relationships of bexarotene with outcomes related to RXRA and RARA activity, corepressor binding, compound stability, and anti-leukemic potential.

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Changes in expression of WT1 during induced differentiation of the acute myeloid leukemia cell lines by treatment with 5-aza-2′-deoxycytidine and all-trans retinoic acid

Oncology Letters ◽

10.3892/ol.2015.4052 ◽

2015 ◽

Vol 11 (2) ◽

pp. 1521-1526 ◽

Cited By ~ 4

Author(s):

LILI XIANG ◽

JIAHE ZHOU ◽

WEIYING GU ◽

RONG WANG ◽

JIANG WEI ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Cell Lines ◽

Myeloid Leukemia ◽

Leukemia Cell ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Leukemia Cell Lines ◽

Acute Myeloid ◽

Myeloid Leukemia Cell

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Proteomic Studies of Primary Acute Myeloid Leukemia Cells Derived from Patients Before and during Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid and Valproic Acid

Cancers ◽

10.3390/cancers13092143 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2143

Author(s):

Maria Hernandez-Valladares ◽

Rebecca Wangen ◽

Elise Aasebø ◽

Håkon Reikvam ◽

Frode S. Berven ◽

...

Keyword(s):

Valproic Acid ◽

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Rna Metabolism ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we used a proteomic/phosphoproteomic strategy to investigate the in vivo effects of ATRA/VP on human AML cells. Before starting the combined treatment, AML responders showed increased levels of several proteins, especially those involved in neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates (i.e., DNA synthesis and binding). Several among the differentially regulated phosphorylation sites reflected differences in the regulation of RNA metabolism and apoptotic events at the same time point. These effects were mainly caused by increased cyclin dependent kinase 1 and 2 (CDK1/2), LIM domain kinase 1 and 2 (LIMK1/2), mitogen-activated protein kinase 7 (MAPK7) and protein kinase C delta (PRKCD) activity in responder cells. An extensive effect of in vivo treatment with ATRA/VP was the altered level and phosphorylation of proteins involved in the regulation of transcription/translation/RNA metabolism, especially in non-responders, but the regulation of cell metabolism, immune system and cytoskeletal functions were also affected. Our analysis of serial samples during the first week of treatment suggest that proteomic and phosphoproteomic profiling can be used for the early identification of responders to ATRA/VP-based treatment.

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