Community Research and Development Information Service - CORDIS



Project ID: 615068
Funded under: FP7-IDEAS-ERC
Country: Sweden

Mid-Term Report Summary - LEUKEMIABARRIER (The Leukemia-Initiating Cell: Genetic Determinants, Escape Mechanisms and Ontogenic Influence)

A main aim of the project is to obtain information on how leukaemia is initiated. This includes determination of the identity of the cells that can result in leukaemia. Towards this goal, we have conducted work that so far has resulted in three publications (Ugale et al, 2014; Velasco et al., 2016; Ugale et al 2017). In the work, we have established that a range of progenitor cells can initiate leukaemia, but highly surspringly, not the most primitive hematopoietic stem sells. In a fourth paper (Jaako et al., 2016), we have adressed the specific mechamism of ribosome biogenesis on leukemia initiation.

As part of our published work, we have generated gene expression profiles of leukemia-initiating cells upon onset of the MLL-ENL oncogene. This data is intersected with new exome-sequencing data that we have generated to identify relevant secondary mutations. We are currently pursuing such gene candidates at a functional level. Very recently, we have conducted chromatin accessilibity studies (using ATAC-seq) on cells in response to MLL-ENL induction, with the aim of intersecting this data with gene expression data.

A second aim of the project is to explore how immunity might restrict leukaemia initiation. We have spent considerable effort in optimizing conditioning regimens, determining cell doses, characterizing in vivo cell depletion strategies and generated appropriate immunodeficient mouse models towards this aim.

In our final aim, we are approaching if age might impact on MLL-ENL leukaemia initiation. We have established the stability of the aging hematopoietic stem cell state; work that also has highlighted also the normal clonal contribtions of hematopoietic stem cells as a consequence of age. This work has recently been accepted for publication (Wahlestedt et al., 2017). As part of this aim, we have also collaborated with the group of Kees-Jan Pronk (Lund University) to provide insights into aging human hematopoiesis.

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