Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression

L. C. Stetson, Dheepa Balasubramanian, Susan Pereira Ribeiro, Tammy Stefan, Kalpana Gupta, Xuan Xu, Slim Fourati, Anne Roe, Zachary Jackson, Robert Schauner, Ashish Sharma, Banumathi Tamilselvan, Samuel Li, Marcos de Lima, Tae Hyun Hwang, Robert Balderas, Yogen Saunthararajah, Jaroslaw Maciejewski, Thomas LaFramboise, Jill S. Barnholtz-SloanRafick Pierre Sekaly, David N. Wald

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC’s) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC’s.

Original languageEnglish (US)
Pages (from-to)2799-2812
Number of pages14
JournalLeukemia
Volume35
Issue number10
DOIs
StatePublished - Oct 2021
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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