The Differentiating Effect of Retinoic Acid and Vincristine on Acute Myeloid Leukemia

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.

Download Full-text

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.

Download Full-text

Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

Therapeutic Advances in Hematology ◽

10.1177/2040620720976984 ◽

2021 ◽

Vol 12 ◽

pp. 204062072097698

Author(s):

Xiaoyan Han ◽

Chunxiang Jin ◽

Gaofeng Zheng ◽

Yi Li ◽

Yungui Wang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

Specific Factor ◽

Acid Receptor ◽

Response To Chemotherapy ◽

Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

Download Full-text

The HER2 inhibitor TAK165 Sensitizes Human Acute Myeloid Leukemia Cells to Retinoic Acid-Induced Myeloid Differentiation by activating MEK/ERK mediated RARα/STAT1 axis

Scientific Reports ◽

10.1038/srep24589 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 13

Author(s):

Xuejing Shao ◽

Yujia Liu ◽

Yangling Li ◽

Miao Xian ◽

Qian Zhou ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Leukemia Cells ◽

Myeloid Differentiation ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

Download Full-text

ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression

Blood ◽

10.1182/blood-2005-07-3068 ◽

2006 ◽

Vol 107 (8) ◽

pp. 3330-3338 ◽

Cited By ~ 139

Author(s):

Beatrice U. Mueller ◽

Thomas Pabst ◽

José Fos ◽

Vibor Petkovic ◽

Martin F. Fey ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Myeloid Leukemia ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

All Trans Retinoic Acid ◽

Conditional Expression ◽

Neutrophil Differentiation ◽

Acute Myeloid

Abstract Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor α (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).

Download Full-text

Chemotherapy and All-Trans Retinoic Acid in Patients >60 Years with Acute Myeloid Leukemia: First Results of the Multicenter Treatment Trial AML HD98-B

Haematology and Blood Transfusion / Hämatologie und Bluttransfusion - Acute Leukemias VIII ◽

10.1007/978-3-642-18156-6_96 ◽

2001 ◽

pp. 604-608 ◽

Cited By ~ 2

Author(s):

S. FröHling ◽

R. F. Schlenk ◽

F. Del Valle ◽

F. Hartmann ◽

A. Glasmacher ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Treatment Trial ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

First Results ◽

Acute Myeloid

Download Full-text

Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid–induced differentiation

Science Advances ◽

10.1126/sciadv.aax2746 ◽

2020 ◽

Vol 6 (15) ◽

pp. eaax2746 ◽

Cited By ~ 5

Author(s):

Roberto Ravasio ◽

Elena Ceccacci ◽

Luciano Nicosia ◽

Amir Hosseini ◽

Pier Luigi Rossi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

H3k4 Methylation ◽

Acute Myeloid Leukemia Cells ◽

Histone H3k4 ◽

Expression Program ◽

Differentiation Gene ◽

Acute Myeloid

The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

Download Full-text

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.

Download Full-text