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Doctoral Thesis
Full name
Isabel Weinhäuser
Knowledge Area
Date of Defense
Ribeirão Preto, 2021
Rego, Eduardo Magalhães (President)
Alves Filho, José Carlos Farias
Souza, Lucas Eduardo Botelho de
Welner, Robert Samuel
Title in English
An M2-polarized macrophage microenvironment drives leukemogenesis and poor prognosis in acute myeloid leukemia
Keywords in English
Clinical outcomes
Phagocytosis evasion
Therapy resistance
Tumor associated macrophages
Abstract in English
While it is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones, the tumor supportive microenvironment (TSM) in acute myeloid leukemias (AML) remains poorly understood. Here, we uncover that patients with the poorest prognosis harbor an M2-polarized macrophage compartment. Coculture of leukemic blasts on M2 macrophages promotes cell survival and drug resistance. Intrabone marrow co-injection of M2- macrophages induces fatal leukemia of acute promyelocytic leukemia blasts, which are otherwise poor grafters. Even a short-term two-day in vitro exposure to M2 macrophages can "train" leukemic blasts after which cells are protected against phagocytosis, display increased mitochondrial metabolism and in vivo homing, resulting in full-blown leukemia. We developed an M2-based biomarker panel that outperforms currently used AML prognosis predictors. Our study provides insight into the mechanisms by which the TSM contributes to aggressive leukemia development and provides alternatives for effective targeting strategies.
Title in Portuguese
Um microambiente de macrófagos polarizados em M2 impulsiona a leucemogênese e o mau prognóstico na leucemia mielóide aguda
Keywords in Portuguese
Desfechos clínicos
Evasão à fagocitose
Macrófagos associados ao tumor
Resistência à terapia
Abstract in Portuguese
Embora esteja cada vez mais claro que os cânceres são uma simbiose de diversos tipos celulares e clones tumorais, o microambiente de suporte tumoral (MST) em leucemias mieloides agudas (LMA) ainda permanece pouco compreendido. Nesse trabalho, nos demonstramos que os pacientes com pior prognóstico contem um compartimento de macrófagos polarizados em M2. A co-cultura de blastos leucêmicos com macrófagos M2 promoveu a sobrevivência celular e a resistência a agentes quimioterapicos. A injeção de macrófagos M2 na medula induziu leucemia fatal em animais transplantados com blastos de leucemia promielocitica aguda, usualmente conhecidos por seu baixo potencial de enxertia. Mesmo a exposição in vitro por dois dias a macrófagos M2, conseguiu "treinar" os blastos leucêmicos, após os quais as células são protegidas contra a fagocitose, apresentam metabolismo mitocondrial e homing in vivo aumentado, resultando em leucemia desenvolvida. Nós desenvolvemos um painel de biomarcadores baseado em macrofagos M2 que supera os preditores de prognóstico para LMA usados atualmente. Nosso estudo fornece uma visão sobre os mecanismos pelos quais o MST contribui para o desenvolvimento de leucemia agressiva e fornece alternativas para estratégias eficazes de tratamento e manejo clinico.
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