Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL))

Küley‐Bagheri, Yasemin; Kreuzer, Karl‐Anton; Monsef, Ina; Lübbert, Michael; Skoez, Nicole

doi:10.1002/14651858.cd011960.pub2

Cited by 18 publications

(16 citation statements)

References 55 publications

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“…The most frequent of these, PML-RARα, does not respond to physiological doses of atRA, yet myeloid differentiation is restored by pharmacological levels of this agent 25 . In contrast, even though atRA also promoted the differentiation of non-APL AML blasts, clinical trials have failed to reveal any clear therapeutic benefit in these patients 26–28 . Certain molecularly or genetically defined subgroups of non-APL AML were suggested to gain a survival advantage from atRA, but no consistent picture has yet emerged 26,27,29,30 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Ecotropic 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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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…In children, acute lymphoblastic leukemia and in adults, AML were the foremost subtype in both sexes (Miranda‐Filho et al, ). Even though leukemia conventional treatment usually are effective, particularly in children, leukemia therapy is deadly and has the ability to harm or disrupt many organ systems normal functions (Kuley‐Bagheri, Kreuzer, Monsef, Lubbert, & Skoetz, ; Mei et al, ). Patients who survive leukemia and its treatment have meaningfully augmented risk for second abnormalities and early mortality from a diversity of reasons, particularly cardiac events (Chellapandian, Pole, Nathan, & Sung, ).…”

Section: Introductionmentioning

confidence: 99%

Leukemia therapy by flavonoids: Future and involved mechanisms

Saraei

Marofi

Naimi

et al. 2018

Journal Cellular Physiology

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Flavonoids are a varied family of phytonutrients (plant chemicals) usually are detected in fruits and vegetables. In this big family, there exist more than 10,000 members that is separated into six chief subtypes: isoflavonols, flavonoenes, flavones, flavonols, anthocyanins, and chalcones. The natural compounds, such as fruits, have visible positive effects in regulating of survival involved signaling pathways that performance as the regulator of cell survival, growth, and proliferation. Researchers have established that commonly consumption up flavonoids decreases incidence and development risk of certain cancers, especially leukemia. Flavonoids have been able to induce apoptosis and stimulate cell cycle arrest in cancer cells via different pathways. Similarly, they have antiangiogenesis and antimetastasis capability, which were shown in wide ranges of cancer cells, particularly, leukemia. It seems that flavonoid because of their widespread approval, evident safety and low rate of side effects, have hopeful anticarcinogenic potential for leukemia therapy. Based on the last decade reports, the most important acting mechanisms of these natural compounds in leukemia cells are stimulating of apoptosis pathways by upregulation of caspase 3, 8, 9 and poly ADP‐ribose polymerase (PARP) and proapoptotic proteins, particularly Bax activation. As well, they can induce cell cycle arrest in target cells not only via increasing of activated levels of p21 and p53 but also by inhibition of cyclins and cyclin‐dependent kinases. Furthermore, attenuation of neclear factor‐κB and signal transducer and activator of transcription 3 activation, suppression of signaling pathway and downregulation of intracellular antiapoptotic proteins are other significant antileukemic function mechanism of flavonoids. Overall, it appears that flavonoids are promising and effective compounds in the field of leukemia therapy. In this review, we tried to accumulate and revise most promising flavonoids and finally declared their major working mechanisms in leukemia cells.

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“…Different trials assessing the efficacy of atRA in AML were based on different chemotherapeutics. atRA was initiated at different time points relative to the start of chemotherapy, and was included in the maintenance therapy in some studies but not others [ 31 ]. Prolonged administration of atRA may be of particular importance in cases where atRA inhibits LSCs.…”

Section: Discussionmentioning

confidence: 99%

“…However, acute promyelocytic leukemia (APL), characterized by rearrangements of the retinoic acid receptor alpha ( RARA ) gene, has benefited more than any other AML subtype from targeted therapies: addition of the RARA ligand all-trans retinoic acid (atRA) to its therapy has greatly improved APL patient survival for the last few decades [ 15 , 16 , 17 ]. Despite the striking success of atRA in APL, and even though atRA also causes blast differentiation and sensitization to chemotherapy in other types of AML in vitro [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], clinical benefit of atRA in non-APL AML has not been consistently demonstrated so far [ 20 , 27 , 28 , 29 , 30 , 31 ]. Further, attempts to identify genetically defined subgroups of patients that may respond to atRA-containing therapy have yielded contradictory results [ 20 , 27 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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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Effects of all-trans retinoic acid (ATRA) in addition to chemotherapy for adults with acute myeloid leukaemia (AML) (non-acute promyelocytic leukaemia (non-APL))

Cited by 18 publications

References 55 publications

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

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

Leukemia therapy by flavonoids: Future and involved mechanisms

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

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