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Acute Myeloid Leukemia Leukemic Initiating Cells: Contribution of hypoxia/HIF pathway to chemoresistance and relapse

Objective

Acute myeloid leukemia (AML) is a heterogeneous group of diseases caused by acquired cytogenetic and molecular alterations in hematopoietic progenitor cells. There is a substantial need to develop new therapeutic approaches to AML; however, the genetic heterogeneity of AML constitutes a barrier for the development of targeted therapies. Leukemia relapse after treatment is most often caused by a subgroup of cells commonly referred to as leukemia initiating cells (LICs), which are resistant to chemotherapy. It is thought that this resistance is the result of several properties unique to LICs, including their dormant and metabolically inactive state, making them less susceptible to genotoxic drugs. The localization of the LICs in the hypoxic bone marrow niche has been proposed as a driving factor for dormancy. The HIF (hypoxia-inducible factor) family of transcription factors mediates cellular adaptation to hypoxia. While the role of HIFs in the pathogenesis of solid tumors is quite well established, they have only recently been suggested as key regulators of LICs in specific types of leukemia. Yet, results to date are highly controversial, with some studies supporting an oncogenic activity for HIFs and others pointing to a tumor suppressor role.

We propose a broad transcriptional study of human AML classified by cytogenetic criteria and disease stage (diagnosis vs relapse). We will focus on HIF-regulated target genes in the LIC subgroup and evaluate LIC heterogeneity using state-of-the-art single-cell technologies. Our results should extend our understanding of the ability of LICs to survive cytotoxic therapy and help to identify candidate targets for clinical application.

The use of AML patient samples and single-cell techniques included in this proposal will increase my scientific knowledge and practical experience. I will also benefit from the complementary planned activities of the action, empowering me to become an independent investigator in the near future.

Fields of science (EuroSciVoc)

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Programme(s)

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Topic(s)

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Funding Scheme

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MSCA-IF-EF-ST - Standard EF

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Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

(opens in new window) H2020-MSCA-IF-2017

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Coordinator

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 158 121,60
Address
CARRETERA DE CAN RUTI CAMI DE LES ESCOLES S/N
08916 Badalona
Spain

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Region
Este Cataluña Barcelona
Activity type
Research Organisations
Links
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 158 121,60
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