TY  - GEN
TI  - Deciphering the Interplay of Acute Myeloid Leukemia
with the Bone Marrow Microenvironment
A1  - Mathioudaki, Anna
CY  - Heidelberg
N2  - Acute myeloid leukemia (AML) is a hematologic malignancy that leads to the accumulation of immature blasts in the bone marrow (BM). The BM is a complex organ, consisting of several cell types, including immune cells as well as non-hematopoietic stromal cells. In AML, chemotherapy may lead to long-term remission, although alloge- neic stem cell transplantation (alloSCT) often remains the only therapeutic strategy. However, not every patient responds to alloSCT and often suffer from relapse due to chemo-resistant leukemic stem cells (LSCs).
One of the hypotheses associated with therapy failure is the incapability of donor T cells to recognize and eliminate LSCs, thus escaping graft-versus-leukemia (GVL) ef- fect. The first objective of this thesis was to investigate the role of T cell in alloSCT therapy outcome. Using single-cell RNA-sequencing (scRNA-seq) on BM T lymphocytes and CD34+ hematopoietic stem and progenitor cells (HSPCs) of six AML patients 100 days after alloSCT, I identified T cell signatures associated with either relapse (REL) or complete remission (CR). Among these signatures, a higher frequency of cytotoxic CD8+ effector and gamma delta T cells was observed in CR versus REL samples. Further analyses revealed that in CR, CD8+ T cells were more mature and characterized by higher cytotoxicity, while in REL CD8+ T cells were characterized by inflammatory TNF/NF-?B signaling as well as an immunosuppressive signature. In addition, this anal- ysis identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells. Ad- ditional flow cytometry analyses in independent patient cohorts suggested GPR56 as a marker of cytotoxicity as well as a marker of antigen encounter post alloSCT. Together, these data provide a single-cell reference map of BM-derived T cells post alloSCT and propose GPR56 expression dynamics as a surrogate for monitoring alloSCT.
One of the key drivers of AML progression is its interaction with the BM stromal microenvironment. In addition, AML is hypothesized to remodel the BM, creating a protective environment for LSCs. Thus, the second objective of this thesis was to study the impact of AML on the microenvironment and the specific contribution of LSCs in this process. For that, I combined scRNA-seq of AML xenograft models and in vitro co- cultures of patient-derived BM mesenchymal stromal cells (MSCs) with AML. These data indicated that AML presence impacts the BM composition, leading to the expansion of Cxcl12-abundant-reticular adipocyte progenitors (Adipo-CAR), decline of osteoblasts as well as disruption of the vasculature. When comparing high LSC-frequency (LSChigh) with low LSC-frequency (LSClow) AML, changes in the abundance of several stromal subsets were detected, suggesting the importance of these populations in LSC expansion. Specifically, LSChigh AML was associated with a decrease in the osteo-lineage and an expansion of multiple fibroblast subsets marked by altered extracellular matrix signa- tures. Furthermore, in vitro co-cultures uncovered similar patterns: upon LSChigh co- culture, human MSCs suppress the expression of osteoblast lineage genes, while over- expressing fibrosis-related genes.
Collectively, the findings outlined in this thesis provide novel insights into the interaction of AML with the BM microenvironment, which has implications in disease progression and therapy outcome. These insights offer new opportunities for identifying intervention targets which may improve AML patient outcome.
Y1  - 2023///
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/33916/
AV  - public
ID  - heidok33916
ER  -