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

BMC Cancer. 2020 Nov 11;20(1):1090. doi: 10.1186/s12885-020-07533-6.

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.

Keywords: AICAr; ATRA; Acute myeloid leukemia; Brequinar; Differentiation.

MeSH terms

  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Blast Crisis / drug therapy*
  • Blast Crisis / genetics
  • Blast Crisis / metabolism
  • Blast Crisis / pathology
  • Bone Marrow / drug effects*
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Case-Control Studies
  • Cell Differentiation*
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • RNA-Seq
  • Ribonucleosides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • Ribonucleosides
  • Aminoimidazole Carboxamide
  • acadesine