RNA-sequencing of acute promyelocytic leukemia primary blasts reveals novel molecular biomarkers of early death events

Abstract

Although acute promyelocytic leukemia (APL) has evolved to the AML entity with the best prognosis, typical ‘early death’ (ED) events still account for mortality rates of ∼20% in population-based studies. To investigate this poorly understood issue we performed whole transcriptome analysis of n = 7 APL ED cases compared to n = 7 APL cases with long term remission. We discovered the proteins S100A8/S100A9 and EFEMP1 as the most differentially expressed factors. In an independent cohort of n = 58 APL patients EFEMP1 over-expression was associated with a worse overall survival. Furthermore, a subgroup analysis of ED caused by hemorrhagic complications revealed an association of metallothioneins (MT1G/MT1E) with higher bleeding rates, ED events and negative prognostic effects on overall survival. Finally, we identified a novel TPM4-KLF2 fusion transcripts in 44/64 APL samples. In summary, we report a comprehensive transcriptomic analysis and novel potential biomarkers of ED biology, which highlight novel pathways in ED events in APL.

Keywords:

• Acute promyelocytic leukemia
• hematology
• early death

Acknowledgments

We thank Helmut Blum for access to sequencing facilities. This work was supported by funds of the Deutsche Forschungsgemeinschaft (DFG), the Gutermuth Foundation, the H.W. & J. Hector foundation (Weinheim), the Dr. Rolf M. Schwiete Foundation (Mannheim). D. N. is an endowed Professor of the German José-Carreras-Foundation (DJCLSH03/01).

Author contributions

J.-C. J., A.S., D.N., W.-K. H. designed the study, analyzed data and wrote the manuscript; A. S. and J.-C. J. conducted experimental design, executed bioinformatic analyses and most of the experiments; D.N. and W.-K.H. supervised the whole study and provided research infrastructure; V.N., J.O., J.P J.D., I.P., and C.K. provided assistance for molecular analyses, A. H., F.N., E.L., and D.N. provided patient material and clinical data.

Disclosure statement

No potential conflict of interest was reported by the author(s).