Advisory Committee Chair
Ravi Bhatia
Advisory Committee Members
Douglas R Hurst
Amjad Javed
Christopher A Klug
Robert S Welner
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Acute myeloid leukemia (AML) is an aggressive, complex hematological malignancy. AML cases with constitutively-activating internal tandem duplications in the Flt3 receptor (Flt3-ITD) represent a distinct subtype of disease with poor prognosis, but unique opportunities for targeted therapy. Flt3-specific tyrosine kinase inhibitors (TKI) have entered clinical practice due to their ability to induce remissions in a large proportion of Flt3-mutant AML patients, but their long-term efficacy remains limited due to the persistence of leukemia stem cells (LSC) in the bone marrow (BM). Herein, we outline the importance of the bone marrow microenvironment (BMM) in harboring LSC through AML development and drug resistance. We describe a new mouse model of Flt3-ITD AML, characterize its LSC phenotype and the LSC phenotype of human samples from AML patients with similar mutations, and use CXCL12 deletion from the BMM to identify p38 MAPK as a potentially targetable mechanism of BMM-induced drug resistance in Flt3-ITD AML. We also characterize the role of various CXCL12-expressing non-hematopoietic BM cell types in Flt3-ITD AML development and drug response. Our data support the hypothesis that Flt3-ITD AML LSC occupy BMM niches distinct from normal HSC, and will guide further study of the role of specific cellular components in LSC survival and drug resistance. Finally, we assess the necessity of Interleukin-1 (IL-1) ligands IL-1α and IL-1β in the development and drug resistance of chronic myeloid leukemia (CML) and Flt3-ITD AML mouse models. Interleukin-1 signaling has been previously iv described as a strong mediator of myeloid leukemia progression and drug resistance, but using IL-1α/β knock-out CML and AML mouse models, we report that IL-1α/β are dispensable for myeloid leukemia development, progression, and drug resistance. It is likely that essential downstream mediators of IL-1 signaling, which include p38 MAPK, may be activated by means other than canonical IL-1α/β signaling. These studies represent important advances in understanding the role of the BMM in supporting LSC drug resistance. We discuss the translational potential of these findings in improving future clinical studies by targeting p38 MAPK in combination with Flt3 TKI, further characterization of the AML LSC niche, and selecting proper techniques for targeting IL-1 signaling.
Recommended Citation
Anderson, Nicholas R., "The Role of the Bone Marrow Microenvironment in FLT3-ITD Acute Myeloid Leukemia Stem Cell Resistance to FLT3 Inhibition" (2022). All ETDs from UAB. 209.
https://digitalcommons.library.uab.edu/etd-collection/209