A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy

Year: 2023

Type: article

Abstract: The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens. SIGNIFICANCE: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949.

Source: Cancer Discovery

DOI: 10.1158/2159-8290.cd-22-1297

Institutions: First Affiliated Hospital Zhejiang University, Zhejiang University, University of Colorado Anschutz, University of Colorado Cancer Center, University of Colorado Denver

Language: English

Topic: Acute Myeloid Leukemia Research

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: U.S. Department of Veterans Affairs, Leukemia and Lymphoma Society, National Natural Science Foundation of China, National Institutes of Health, Anschutz Medical Campus, University of Colorado, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases

Awards: G1198253935, G1360078345, G1625418467, G1807469355, G2833788466, G3568501360, G3732328562, G5970797882, G6241773839, G6245591484, G806246556, G9000030515, G9000141685, G9000152846, University of Colorado Cancer Center Support Grant

OpenAlex ID: W4382010567