The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NF-κB signaling
Abstract
Abstract Acute myeloid leukemia (AML), an aggressive hematological malignancy, is driven by oncogenic mutations in stem and progenitor cells that give rise to AML blasts. Although these mutations are well characterized, their impact on healthy hematopoiesis, those blood cells exposed to AML but not mutated, has not been well characterized. Because the marrow is the major site for granulopoiesis, neutrophils are heavily influenced by AML pathobiology. Indeed, most patients with AML report neutropenia, rendering them susceptible to infections. However, because AML studies use peripheral blood mononuclear cells devoid of neutrophils, the characterization of neutrophil dysfunction remains poorly understood. To investigate AML-exposed neutrophils, a preclinical AML mouse model in which primary leukemic cells were transplanted into nonirradiated neutrophil reporter (Ly6G-tdTomato; Catchup) hosts was used. Neutrophils could not completely mature, suggesting impaired granulopoiesis. Single-cell transcriptomics of AML-exposed neutrophils revealed higher inflammation signatures and expression of CD14, an inflammatory marker. To address the factors contributing to this biology, an ex vivo cytokine screen was performed on marrow neutrophils, and it identified that nuclear factor κB signaling drove CD14 expression. AML-exposed neutrophils displayed widespread chromatin remodeling, and de novo motif discovery predicted increased binding sites for CCAAT enhancer–binding proteins and interferon regulatory factors. Moreover, AML-exposed neutrophils inhibited T-cell proliferation, highlighting their immune-suppressive capability. Finally, a similar biology of immature, inflammatory neutrophils was found in patients with AML, again indicating dysregulated granulopoiesis. Collectively, these data show that AML-associated inflammation alters neutrophil granulopoiesis, impairs neutrophil function, and drives immunosuppression, thereby contributing to patient susceptibility to infection.
Article Details
Authors (25)
Paran Goel
1University of Alabama, Birmingham, Birmingham, United States
Sajesan Aryal
1University of Alabama at Birmingham, Birmingham, United States
Alana M. Franceski
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Valeriya Kuznetsova
2The University of Alabama at Birmingham, Birmingham, United States
Amanda Costa
1University of Alabama, Birmingham, Birmingham, United States
Francesca Luca
Department of Clinical and Biological Science, University of Torino
Ashley N. Connelly
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Daniel W. Phillips
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Caroline C. Ennis
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Brittany M. Curtiss
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Sourajeet Karfa
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Brittany L. Crown
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Christina R. Larson
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Estelle Carminita
1Boston Children's Hospital, Vascular Biology Program, Boston, United States
Virginia Camacho
1Boston Children's Hospital, Vascular Biology Program, Boston, United States
Doug Welsch
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
Changde Cheng
1University of Alabama, Birmingham, Birmingham, United States
Asumi Yokota
5Laboratory of Stem Cell Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
Isidoro Cobo
University of Alabama at Birmingham, Birmingham, Alabama, United States
Hideyo Hirai
Tokyo University of Pharmacy and Life Sciences
Rui Lu
Ravi Bhatia
1University of Alabama at Birmingham, Birmingham, United States
Pran K. Datta
1Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, Birmingham, AL
P. Brent Ferrell
7Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
Robert S. Welner