Single-cell Chromatin Accessibility Profiling of Acute Myeloid Leukemia Reveals Heterogeneous Lineage Composition Upon Therapy-resistance

Overview

Journal Commun Biol

Specialty Biology

Date 2023 Jul 21

PMID 37479893

Authors

Huihui Fan

Feng Wang

Andy Zeng

Alex Murison

Katarzyna Tomczak

Dapeng Hao

Fatima Zahra Jelloul

Bofei Wang

Praveen Barrodia

Shaoheng Liang

Ken Chen

Linghua Wang

Zhongming Zhao

Kunal Rai

Abhinav K Jain

John Dick

Naval Daver

Andy Futreal

Hussein A Abbas

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy.

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