Molecular and functional characterization of the interplay between malignant and stromal cells in acute myeloid leukemia and myelodysplastic syndrome

Corradi, Giulia (2019) Molecular and functional characterization of the interplay between malignant and stromal cells in acute myeloid leukemia and myelodysplastic syndrome, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie, 31 Ciclo.
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Abstract

In this thesis, we studied the cross-talk between malignant cells and stromal cells, with the aim to elucidate the respective contribution to myeloid neoplasm onset and progression. First, we characterized and compared mesenchymal stromal cells (MSCs) isolated from myelodysplastic syndrome (MDS-MSCs) and acute myeloid leukemia (AML-MSCs) patients. We demonstrated that, despite some unaltered functions, patient-derived MSCs show also intrinsic, distinct functional abnormalities, which could all potentially favor a leukemia-protective bone marrow (BM) niche in vivo. Second, we investigated the ability of AML cells to modulate the AML-MSC functions. In a GEP-screening, we found that 40% of BM-derived AML samples show a higher IFN-γ expression, compared to the mean IFN-γ expression in healthy BM-derived cells. We demonstrated that in co-culture experiments, IFN-γ+ AML cells modify AML-MSC gene expression and function, inducing the up-regulation of IDO1, and consequently the generation of T regulatory cells. Finally, we wondered if the transcriptome of stromal cells could be influenced by the hematopoietic-specific alterations, i.e. Dnmt3a and Asxl1 mutations, which occur early in MDS/AML patients. We found that Dnmt3a- and Asxl1-null BM cells, when transplanted in wild-type mice, induce profound and deletion-specific modifications in the transcriptome of wild-type BM stromal cells, suggesting the ability of Dnmt3a- and Asxl1-null BM cells to shape the niche. Furthermore, we compared the transcriptome of wild-type BM stromal cells, obtained from transplantation experiments, with that of MSCs isolated from low-risk MDS patients with DNMT3A and ASXL1 mutations, and we highlighted some common modifications, which could be potentially relevant for human disease and specific for DNMT3A/ASXL1 mutations. In conclusion, this thesis pointed out that there is a bi-directional cross-talk, in which stromal cells can influence malignant cells, and in turn malignant/pre-malignant cells can alter stromal cell gene expression and function. Both mechanisms could potentially contribute to the pathogenesis of myeloid malignancies.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Corradi, Giulia
Supervisore
Co-supervisore
Dottorato di ricerca
Ciclo
31
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), mesenchymal stromal cells (MSCs), bone marrow (BM) microenvironment, IDO1, DNMT3A, ASXL1
URN:NBN
Data di discussione
12 Aprile 2019
URI

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