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H2020Individual fellowship2016–2018

NovLeuReg · Identification and characterization of novel essential regulators of acute myeloid leukemia

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-04-01 → 2018-09-02
EU contribution
€212,195
Participants
1
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

Identification and characterization of novel essential regulators of acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy characterized by the uncontrolled proliferation of immature myeloid cells. Currently, there is no unified treatment approach for AML, and the mortality rate remains high. Epigenetic regulators represent good targets for the development of future personalized therapies due to their frequent mutations in AML and their drug-ability. In this project we aimed to identify novel essential epigenetic regulators of AML by means of loss-of-function genetic screens. Firstly, we have established novel mouse models of normal karyotype AML by combining most frequently occurring human AML mutations. Next, we performed CRISPR knockout screens in those models and identified several potential regulators of this AML subtype. In parallel, we have optimized a CRISPR interference technique for loss-of-function pooled screening and performed screens in human MLL-AF9 rearranged AML cell lines. This revealed important regulators of this AML group, which we further extensively characterized molecularly. The carried-out work provides new insights into the biological functions of the identified screen hits and uncovers the mechanisms leading to leukemia progression and maintenance. This, in turn, will contribute to the development of new therapies for the treatment of cancer patients. In addition to scientific and medical advancement, the accomplishment of the study equipped the main researcher with a unique set of research ideas, techniques, reagents and collaborations necessary to establish herself as an independent group leader.

Data: CORDIS, © European Union

Project objective

Acute myeloid leukemia is a hematopoietic malignancy characterized by the abnormal proliferation of immature myeloid cells. The implementation of high-throughput sequencing revealed that somatic mutations in various epigenetic regulators represent a frequent pathogenic phenomenon in leukemogenesis. This raised optimism for the development of new therapies in leukemia due to the reversible nature of epigenetic marks and amenability of chromatin-modifying enzymes to pharmacological inhibition. However, realization of this potential requires further research into epigenetic mechanisms governing the maintenance of leukemic cells. The overall goal of the proposed work is to characterize novel important epigenetic regulators in leukemic cells and to assess their potential as drug targets. Firstly, I plan to identify and study epigenetic regulators essential for leukemic cells deficient in TET2, an enzyme that hydroxylates methylated cytosines in DNA. This will be achieved by performing state-of-the-art shRNA screens in mouse Tet2-null leukemia models and by exploring the functions of the uncovered candidates using a range of cell biology, biochemistry, and functional genomics approaches. The second aim is to investigate the molecular functions of SETD5, a newly-uncovered epigenetic regulator of leukemic cells. This will be achieved by identifying its target genes and interacting partners in leukemic cells and by exploring the effects of its depletion on normal and cancer cells. The accomplishment of both research aims will provide new insights into epigenetic regulation of leukemic cells and highlight novel drug targets for future therapy development. The project will be supervised by Prof Kristian Helin, a world-leading expert in the field of epigenetics and cancer. Through this work, I aim to broaden my scientific expertise by acquiring numerous technical and transferable skills and to establish myself as an independent researcher in the field of cancer epigenetics.

Original text from CORDIS.

Participants

  • KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark

Links

Data: CORDIS, © European Union