Single cell transcriptomics analysis revealed discriminatory features of differential decitabine response in complex karyotype acute myeloid leukemia patients

Abstract

Decitabine is a DNA methyltransferase inhibitor which is FDA approved for treatment of myeloid malignancies. Despite its efficacy, the molecular mechanism of its induced response in blood cancers is not completely understood. We study decitabine response in acute myeloid leukemia patients using single cell RNA sequencing of serial samples whilst these patients undergo decitabine treatment. Like solid tumors, decitabine treatment induces stronger upregulation of endogenous retroviruses (ERVs) in cancerous cells of responders. We found that expression of dsRNA receptor DHX9 is consistent and abundant on decitabine treatment in both responsive and unresponsive patients, but interferon-regulator factor 7 (IRF7) and several interferon inducible genes showed higher increase in leukemic cells of post-treatment responders, indicating stronger interferon mediated immune response in leukemic cells of responders making them more conspicuous to immune surveillance. Specifically, trajectory analysis in leukemic cells along erythroid differentiation lineage indicated greater upregulation of MHC class II genes in differentiated cells in responding patients. It would contribute to increased recognition of these cells by the immune system and result in the observed greater reduction of these cells. All together our study supports the known drug action of transposable element upregulation on decitabine treatment and extends it to leukemias. More importantly, the high correlation between ERVs’ expression, more activated immune system, and better decitabine outcomes throws new light on AML treatment.