RNA Targeting in Acute Myeloid Leukemia

Alessandra Messikommer; Katja Seipel; Stephen Byrne; Peter J M Valk; Thomas Pabst; Nathan W Luedtke

doi:10.1021/acsptsci.0c00120

RNA Targeting in Acute Myeloid Leukemia

ACS Pharmacol Transl Sci. 2020 Oct 12;3(6):1225-1232. doi: 10.1021/acsptsci.0c00120. eCollection 2020 Dec 11.

Authors

Alessandra Messikommer¹, Katja Seipel², Stephen Byrne¹, Peter J M Valk³, Thomas Pabst², Nathan W Luedtke^{1

4

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Affiliations

¹ Department of Chemistry, University of Zurich, CH-8057 Zurich, Switzerland.
² Department of Medical Oncology, University Hospital Inselspital and University of Bern, CH-3010 Bern, Switzerland.
³ Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands.
⁴ Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada.
⁵ Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3A 1A3, Canada.

Abstract

Nucleosides and their analogues constitute an essential family of anticancer drugs. DNA has been the presumptive target of the front-line prodrug for acute myeloid leukemia (AML), cytarabine (ara-C), since the 1980s. Here, the biomolecular targeting of ara-C was evaluated in primary white blood cells using the ara-C mimic "AzC" and azide-alkyne "click" reactions. Fluorescent staining and microscopy revealed that metabolic incorporation of AzC into primary white blood cells was unexpectedly enhanced by the DNA polymerase inhibitor aphidicholine. According to RNaseH digestion and pull-down-and-release experiments, AzC was incorporated into short RNA fragments bound to DNA in peripheral blood monocytes (PBMCs) collected from all six healthy human donors tested. Samples from 22 AML patients (French-American-British classes M4 and M5) exhibited much more heterogeneity, with 27% incorporating AzC into RNA and 55% into DNA. The overall survival of AML patients whose samples incorporated AzC into RNA was approximately 3-fold higher as compared to that of the DNA cohort (p ≤ 0.056, χ² = 3.65). These results suggest that the RNA primers of DNA synthesis are clinically favorable targets of ara-C, and that variable incorporation of nucleoside drugs into DNA versus RNA may enable future patient stratification into treatment-specific subgroups.