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01-12-2020 | Acute Myeloid Leukemia | Research article

5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts

Authors: Vilma Dembitz, Hrvoje Lalic, Ivan Kodvanj, Barbara Tomic, Josip Batinic, Klara Dubravcic, Drago Batinic, Antonio Bedalov, Dora Visnjic

Published in: BMC Cancer | Issue 1/2020

Abstract

Background

All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA.

Methods

Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0.

Results

AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage.

Conclusion

AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.

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Title: 5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts
Authors: Vilma Dembitz
Hrvoje Lalic
Ivan Kodvanj
Barbara Tomic
Josip Batinic
Klara Dubravcic
Drago Batinic
Antonio Bedalov
Dora Visnjic
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Acute Myeloid Leukemia
Acute Promyelocytic Leukemia
Published in: BMC Cancer / Issue 1/2020
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-020-07533-6

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