Project description
Early detection and treatment of myeloid malignancies
As we age, our body’s blood-producing stem cells, known as Hematopoietic Stem and Progenitor Cells (HSPCs), accumulate mutations that can lead to serious health issues. These mutations, called preleukemic mutations (pLMs), set the stage for clonal hematopoiesis (CH) and increase the risk of developing myeloid malignancies, such as leukaemia. Despite the clear connection between CH and cancer, predicting who will develop these diseases remains a challenge. Current tools are limited in diagnosing these conditions early. The ERC-funded UDEMC project aims to develop cutting-edge diagnostics, understand the molecular impacts of pLMs, and identify therapies that can target preL-HSPCs. Through these efforts, the project hopes to transform how myeloid malignancies are detected and treated.
Objective
As humans age, Hematopoietic Stem and Progenitor Cells (HSPCs) accumulate preleukemic mutations (pLMs), forming preleukemic HSPCs (preL-HSPCs) and leading to clonal hematopoiesis (CH). While the link between CH and myeloid malignancies is established, predicting progression remains elusive. The Shlush lab aims to enhance myeloid malignancies outcomes through early diagnosis and treatment. Still, it faces three gaps: 1) lacking advanced tools for diagnosis/risk stratification beyond mutations, 2) insufficient understanding of pLMs functional consequences, and 3) absence of targeted therapies against pLMs.
To address these challenges, our proposed specific aims are as follows:
Aim 1: Develop a novel diagnostic tool for myeloid leukemia using single-cell RNA sequencing (scRNAseq) of peripheral blood HSPCs from 1300 patients and replace bone marrow (BM) analysis in the future. Such a cohort will allow the discovery of novel mechanisms in leukemia and improved diagnostics.
Aim 2: Create an in vitro assay to explore molecular and functional consequences of human pLMs at the single-cell level, considering self-renewal and changing microenvironments.
Aim 3: Identify drugs targeting human preleukemic HSPCs through a high-throughput drug screen of human preL-HSPCs. This novel approach aims to pave the way for targeted early interventions.
To make these goals feasible the Shlush lab made three major steps forward: 1) created the first reference map of peripheral blood (PB) HSPCs from 150 healthy individuals. 2) developed a dynamics bone marrow in a dish allowing the study of human preL-HSPCs. 3) developed the apoptosis score for detecting apoptosis in a small number of preL-HSPCs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics RNA
- medical and health sciences clinical medicine oncology leukemia
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-COG
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7610001 Rehovot
Israel
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