Chemoresistance in acute myeloid leukemia: An alternative single‐cell RNA sequencing approach

• Published in: Hematological oncology Vol. 41; no. 3; pp. 499 - 509
• Main Authors: Cheng, Po‐Liang, Hsiao, Tzu‐Hung, Chen, Chung‐Hsing, Hung, Miao‐Neng, Jhan, Pei‐Pei, Lee, Li‐Wen, Wu, Ting‐Shuan, Tsai, Jia‐Rung, Teng, Chieh‐Lin Jerry
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2023
• Subjects: Acute myeloid leukemia; Biomarkers; CD9 antigen; Cell differentiation; Chemoresistance; Gene sequencing; Genetic markers; Hematopoiesis; Hematopoietic stem cells; Hemopoiesis; Leukemia; leukemia stem cells; Myc protein; Oxidative phosphorylation; Phosphorylation; Progenitor cells; Remission; Ribonucleic acid; RNA; single‐cell RNA‐seq; Stem cells; TOR protein; single-cell RNA-seq; chemoresistance; leukemia stem cells; acute myeloid leukemia
• ISSN: 0278-0232; 1099-1069; 1099-1069
• DOI: 10.1002/hon.3129

Our previous study demonstrated that myc, mitochondrial oxidative phosphorylation, mTOR, and stemness are independently responsible for chemoresistance in acute myeloid leukemia (AML) cells. This study aimed to identify potential mechanisms of chemoresistance of the “7 + 3” induction in AML by using a single‐cell RNA sequencing (scRNA‐seq) approach. In the present study, 13 untreated patients with de novo AML were enrolled and stratified into two groups: complete remission (CR; n = 8) and non‐CR (n = 5). Single‐cell RNA sequencing was used to analyze genetic profiles of 28,950 AML cells from these patients; results were validated using a previously published bulk RNA‐seq dataset. Our study results showed chemoresistant AML cells had premature accumulation during early hematopoiesis. Hematopoietic stem cell‐like cells from the non‐CR group expressed more leukemic stem cell markers (CD9, CD82, IL3RA, and IL1RAP) than those from the CR group. Chemoresistant progenitor cells had impaired myeloid differentiation owing to early arrest of hematopoiesis. Notably, AML cells analyzed by scRNA‐seq and bulk RNA‐seq harbored a comparable myeloid lineage cell fraction, which internally validated our results. Using the TCGA database, our analysis demonstrated that patients with AML with higher expression of chemoresistant genetic markers (IL3RA and IL1RAP) had a worse overall survival (p < 0.01 for IL3RA; p < 0.05 for IL1RAP). In conclusion, AML cells responsive and resistant to the “7 + 3” induction were derived from a diverse cancerous hematopoietic stem cell population, as indicated by the specific genetic biomarkers obtained using scRNA‐seq approach. Furthermore, arrest of hematopoiesis was shown to occur earlier in chemoresistant AML cells, furthering the current understanding of chemoresistance in AML.