TY - JOUR
T1 - Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression
AU - Stetson, L. C.
AU - Balasubramanian, Dheepa
AU - Ribeiro, Susan Pereira
AU - Stefan, Tammy
AU - Gupta, Kalpana
AU - Xu, Xuan
AU - Fourati, Slim
AU - Roe, Anne
AU - Jackson, Zachary
AU - Schauner, Robert
AU - Sharma, Ashish
AU - Tamilselvan, Banumathi
AU - Li, Samuel
AU - de Lima, Marcos
AU - Hwang, Tae Hyun
AU - Balderas, Robert
AU - Saunthararajah, Yogen
AU - Maciejewski, Jaroslaw
AU - LaFramboise, Thomas
AU - Barnholtz-Sloan, Jill S.
AU - Sekaly, Rafick Pierre
AU - Wald, David N.
N1 - Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s41375-021-01338-7
DO - 10.1038/s41375-021-01338-7
M3 - Article
C2 - 34244611
AN - SCOPUS:85109911986
SN - 0887-6924
VL - 35
SP - 2799
EP - 2812
JO - Leukemia
JF - Leukemia
IS - 10
ER -