Full text
| |
| Author(s): |
Brunno Gilberto Santos de Macedo
Total Authors: 1
|
| Document type: | Master's Dissertation |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2024-01-17 |
| Examining board members: |
Fabíola Traina
|
| Advisor: | Fabíola Traina |
| Abstract | |
Acute myeloid leukemia (AML) is a group of clonal hematological cancers which pathogenesis resides on hematopoietic stem and progenitor cells acquisition of multiple genetic and epigenetic alterations. The molecular alterations that drive AML, besides providing the cells with aberrant stemness and enhanced fitness, are known for rewiring biological processes and promote bone marrow tissue and biochemical architecture remodeling into a leukemiafavorable environment to support tumor functions and assure its progression and maintenance. Autophagy is among the biological processes that are notably rewired to endorse AML cells survival. Autophagy is a conserved lysosome-dependent catabolic process that allows the cells to adapt to several stressors as starvation, damaged or senescent organelle, and, most importantly, oxidative stress. In AML, leukemic stem cells are especially reliant on autophagy to harmonize their metabolic behavior with their energy demands and maintenance of a lower oxidative stress. Mitophagy is actively prompted to keep a constitutive mitochondrial turnover and avoid differentiative stress that could promote leukemic stem cells exhaustion. Several pieces of evidence have also pointed out that the inflammatory status plays a crucial role upon clonal selection and evolution towards myeloid neoplasms. Inflammasomes are cytoplasmic protein complexes and the main sources of interleukin-1β, cytokine described to be associated with beneficial features to AML cells and suppression of normal hematopoiesis. Autophagy and inflammasome were observed to be integrated processes in normal cells. Autophagy removes important inflammasome activators, and autophagy failure is a hallmark event for agerelated inflammatory diseases. We question whether and how autophagy and inflammasome interact molecular and functionally in AML and if this interaction can be leveraged to substantiate clinical improvements. By employing publicly available data from AML cohorts, we have observed strong and positive correlation between autophagy and inflammasome central genes expression, which we argue to be an indicative of mutual regulatory relationship. The transcriptional deconvolution analyses have shown that both malignant cells and stromal cells with molecular signatures compatible with monocytic compartments were mostly responsible for autophagy and inflammasome genes expression. Gene set enrichment analysis of FLT3-ITD samples has provided molecular insights on how autophagy and inflammasome are consistently associated with poor response to the FLT3 inhibitors, and are a predictive factor strongly associated with a poorer ex vivo response phenotype. Even though we were not able to reproduce cell viability observations in vitro using MOLM13 FLT3-ITD AML cell model, we have found that metabolic stress is an important factor for differential interleukin-1β production, and non-canonical inflammasome activation is also present in AML. These findings might substantiate further investigations as means to deepen knowledge on how highly conserved survival mechanisms within tumor cells and microenvironmental remodelling might interact between themselves and how they can improve clinical management, and decisionmaking to support therapy strategies that promotes a more comprehensive approach to a complex and highly heterogeneous disease as AML. (AU) | |
| FAPESP's process: | 22/03871-1 - Functional and molecular investigation of the correlation between autophagy, NLRP3-inflammasome and hemostasis on acute myeloid leukemia |
| Grantee: | Brunno Gilberto Santos de Macedo |
| Support Opportunities: | Scholarships in Brazil - Master |