Sdílet
The mechanisms of signalling pathways deregulation in acute myeloid leukaemia
Doctoral study program
Biomedical Sciences (Faculty of Medicine, Masaryk University)
Study plan
Molecular Medicine
Form of study
doctoral full time /combined
Department
CEITEC MU and Dept of Internal Medicine, Hematology and Oncology
Supervisor
Consultant
prof. Marek Mraz, MSc., MD, Ph.D.
Annotation
Acute myeloid leukemia (AML) is the most aggressive type of leukemia, with a five-year survival rate of approximately 25%. This highly heterogeneous disease is characterized by the abnormal proliferation and accumulation of myeloid precursors in the blood and lymphoid tissues. Current knowledge indicates that conventional treatment strategies, primarily relying on chemotherapy, preferentially target highly proliferative AML cells but often fail to eliminate those exhibiting markers of stemness and quiescence, allowing them to drive disease relapse. Importantly, despite the high cellular diversity, relapsed AML cells share common features in the activity of specific signaling networks, essentially forming a distinct fingerprint of selected subpopulations post-chemotherapy. Therefore, a detailed understanding of the molecular pathways that AML cells utilize to evade chemotherapy holds significant therapeutic potential.
To uncover these molecular mechanisms, we analyzed available RNA-seq data from primary samples before treatment and after relapse. Based on this analysis, we selected several candidates whose functional roles in AML pathophysiology are currently being investigated. Notably, we identified that one of these candidates positively regulates FLT3 signaling, which is significant because FLT3 signaling governs the proliferation and survival of AML cells and is often mutated in AML patients, leading to a more aggressive form of the disease. Currently, we are developing a novel inhibitor of this candidate molecule and plan to experimentally test its therapeutic potential.
In this project, the PhD student will utilize a range of molecular biology techniques (including BioID, immunoblotting, qPCR, transfections, cloning, viral transductions, CRISPR, RNA-seq, and mouse models) to map the protein interactome of the selected candidate and validate the functional significance of these interactions. We plan to use various AML cell lines as well as primary AML samples.
Recommended literature
- Grafone et al., An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev. 2012 Apr 17;6(1):e8. doi: 10.4081/oncol.2012.e8. eCollection 2012 Mar 5.
- Seda et al., FoxO1-GAB1 axis regulates homing capacity and tonic AKT activity in chronic lymphocytic leukemia. Blood. 2021 Sep 2;138(9):758-772. doi: 10.1182/blood.2020008101.
- Döhner et al., Towards precision medicine for AML. Nat Rev Clin Oncol. 2021 Sep;18(9):577-590. doi: 10.1038/s41571-021-00509-w. Epub 2021 May 18.
- Carter et al., Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther. 2020 Dec 18;5(1):288. doi: 10.1038/s41392-020-00361-x.
- Petti et al., Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia. Blood Cancer Discov. 2022 Jan;3(1):32-49. doi: 10.1158/2643-3230.BCD-21-0050. Epub 2021 Aug 24.
Research area
Cancer biology
Keywords
AML, leukaemia, microenvironment, signalling pathways
Funding of the PhD candidate
Part-time salary (min. 0,5 FTE) on EHA/AZV/GACR grants + national scholarship (equals approx. half-time salary); guaranteed net income after taxes of min. 25.000 CZK
Requirements for candidate
- Master’s degree in Molecular biology, Immunology, Physiology or similar field
- Smart and motivated person that work independently, but also willing to learn from other people in the lab and collaborate.
- Desire to learn new things
- Experience of working in a laboratory
Information about the supervisor
Eleven years of experience in leukemia research; H-index 10 (>670 citations); patent: 1; Supervisor of 1 diploma and 1 bachelor thesis; Co-supervisor of 3 diploma and 1 bachelor thesis. Reviewer in scientific journals: Blood Cancer Journal, Frontiers in Oncology. Internship at Centre Esther Koplowitz in Subero lab, Spain. Genome Engineering: CRISPR/ Cas course at European Molecular Biology Laboratory (EMBL), Germany. Holder of Certificate of professional competence to work with animals. Holder of several awards: Young Investigator meeting iwCLL, Purkyně foundation, League against cancer, MUNI scientist award and CEITEC award. Grant award from European hematology association (EHA) for young investigators.
Lab funded by prestigious grants (ERC, EHA, AZV, GAČR)
More information about the research group: http://mrazlab.ceitec.cz/