Advisor(s)
Robert Welner
Christopher Klug
Committee Member(s)
Allan Zajac
Chander Raman
Christian Faul
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
1-6-2025
Abstract
Chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are blood malignancies characterized by clonal expansion and a compromised immune system. Tyrosine kinase inhibitors (TKI) revolutionized CML treatment; however, TKI discontinuation leads to relapses in half of the cases. Further, up to 10% of patients are TKI-resistant and develop a blast crisis resembling AML. Natural killer (NK) cells can clear malignant cells, representing a promising immunotherapy. However, NK cell activity is suppressed in leukemia, and the microenvironmental drivers of this impairment remain understudied. Despite this, the existing mouse models have not been tested to assess the effect of CML on non-mutant NK cells. Here, we demonstrate that NK cells in chimeric BCR::ABL1+ CML mice recapitulate the biology of high-risk patients' NK cells, including reduced counts, altered phenotype, and decreased maturation and cytotoxicity. Next, we found that pro-inflammatory cytokines induce NK cell exhaustion, and TNFα was predicted to be the key contributor. Targeting cytokine-induced checkpoint Cish partially restored the negative effect of leukemic milieu on NK cell cytotoxicity ex vivo. Further, NK cells from newly diagnosed CML patients pre-destined for blast crisis showed enrichment of the identified cytokine-induced gene signature compared to patients who responded to TKI, highlighting the role of inflammation in NK cell perturbation. The development of more effective AML therapies is hindered by the high heterogeneity of this adverse disease. Here, we aimed to uncover the mechanisms underlying NK cell dysfunction in patients with different risk categories stratified by the presence of the common AML mutation, FLT3(ITD). We observed a stressed signature with the activation of TNFα/NFκB signaling pathway and the imbalanced surface receptor expression in NK cells in the high-risk NPMwtFLT3mut cohort. Besides, these NK cells exhibited higher expression of TNFα receptor TNFRSF1B, highlighting the potential role of this axis in NK cell impairment. Overall, these results suggest that the TNFα-induced pro-inflammatory signature is associated with deep NK cell perturbations in high-risk AML and CML, and that targeting aberrant cytokine signaling could enhance NK cell fitness in myeloid malignancies. This work can help endure NK cell-based immunotherapies to secure better outcomes in AML and CML.
ProQuest ID
Recommended Citation
Kuznetsova, Valeriya, "Chronic Inflammation Compromises Natural Killer Cell Phenotype And Function In Myeloid Leukemia" (2025). All ETDs from UAB. 7244.
https://digitalcommons.library.uab.edu/etd-collection/7244
