Advisor(s)
Robert Welner
Committee Member(s)
Christopher Klug
Eric Ubil
Etty Benveniste
Laurie Harrington
Document Type
Dissertation
Date of Award
6-1-2026
Degree Name
Doctor of Philosophy (PhD)
School
Joint Health Sciences (Interdisciplinary)
Department
Cell Biology
Abstract
Acute Myeloid Leukemia (AML) is an aggressive hematopoietic malignancy defined by the accumulation of immature myeloid blasts that fail to differentiate into functional immune cells. The expansion of these blasts disrupts normal hematopoiesis, leading to neutropenia, anemia and thrombocytopenia, causing high susceptibility to infection. Despite established morphological and genetic classification systems, AML remains highly heterogeneous and is difficult to treat clinically. Beyond intrinsic blast heterogeneity, the AML microenvironment profoundly reshapes bystander innate immune cells, influencing disease progression and clinical outcome. One such innate immune cell affected by AML are neutrophils. Using a non-irradiated neutrophil-reporter mouse model, we demonstrated that leukemic burden disrupts steady-state granulopoiesis, resulting in the accumulation of immature neutrophils. Single-cell RNA sequencing revealed that AML-exposed neutrophils adopt a pro-inflammatory transcriptional program marked by aberrant CD14 expression and activation of NF-κB signaling. Functionally, these neutrophils suppressed T cell proliferation, indicating acquisition of immunoregulatory properties. Importantly, similar immature and inflammatory neutrophil populations were identified in AML patient samples, establishing translational relevance and demonstrating that leukemic inflammation reprograms granulopoiesis to weaken host immune defenses. Another innate immune cell perturbed during AML are NK cells. We characterized NK cell alterations at AML diagnosis using high-dimensional flow cytometry and single-cell RNA sequencing. Distinct blast differentiation states were associated with reduced NK cell frequencies and divergent transcriptional programs. Remission correlated with an NF-κB–driven activation signature, whereas relapse was associated with interferon-dependent dysfunction. Leveraging these findings, we developed the Multi-marker AML-NK Relapse Risk Score (MARRS), integrating NK activation and exhaustion markers to predict progression-free survival across independent cohorts. The MARRS metric reliably predicted disease outcomes within a two-year period following diagnosis in both discovery and validation cohorts, highlighting the clinical value of this metric. Together, these studies demonstrate that AML actively reprograms bystander innate immunity and establish immune-based phenotyping as a clinically meaningful strategy for prognostic stratification.
Keywords
Cancer;Immunity;Inflammation;Leukemia
ProQuest ID
Recommended Citation
Goel, Paran, "Systemic Inflammation In Acute Myeloid Leukemia Compromises The Innate Immune System Rendering Patients Susceptible To Infection And Relapse" (2026). ETDs from 2020-2029. 232.
https://digitalcommons.library.uab.edu/etd-2020s/232
