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Molecular pathogenesis of atypical CML: Converting NGS-obtained data into therapeutically relevant information.
Universita degli Studi di Milano-Bicocca
Hematology – Milano Bicocca University Via Cadore 48, Monza (MB)
Prof. Maria Grazia Valsecchi
Prof. Carlo Gambacorti Passerini/ Prof. Rocco Piazza
Type of Research Project
- Clinical Project with Laboratory work
What is the background of the project?
Hematologic neoplasias represent the fifth cancer by mortality. Myeloid leukemias account for the biggest portion of it. The application of Next Generation Sequencing (NGS) to cancer resulted in tremendous progresses in our understanding of its molecular pathogenesis but has not yet proven a substantial therapeutic clinical benefit to patients. Part of the problem stems from the complexity of the interactions among the different genetic alterations present inside each tumor, especially when the initial event does not involve a potent oncogene and is not a direct target for therapeutic intervention. This application will test the hypothesis that tools can be develop, which will allow to overcome at least in part such a hurdle.
What is the aim of the project?
Our project will focus on atypical Chronic Myeloid Leukemia (aCML). NGS-derived information will be used to better define the molecular pathogenesis of aCML and to develop, validate and test rationally designed treatment schemes.
What techniques and methods are used?
State-of-the-art: high throughput sequencing (HTS) technologies such as Whole-Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) will allow us to detect somatic variants occurring at exome level as well as splicing variants, to identify chromosomal translocations/fusion genes, and to produce gene expression profiles. This part will constitute the First and Second Tasks of this project. We will also genotype single-cell-derived hematopoietic colonies, to clarify the order of mutation acquisition and the dynamics of clonal expansion during tumor progression. In addition, such a methodology will be validated using single cell sequencing. Passenger mutations will be filtered out (Third Task). Signal transduction pathways altered in the different patients will also be studied in order to identify pathways involved (Fourth Task). This information will then be used to build in vivo models representing the different patients, thus allowing us to test rationally devised combination treatments and to compare them to standard cytotoxic approaches (Fifth Task). In the Sixth Task, to be activated after the initial 3 years of the project, a pilot clinical study will translate this knowledge into rationally targeted therapy in aCML (atypical Chronic Myeloid Leukemia) patients. The experimental data will be analyzed by a variety of statistical methods such as Student T-test for continous variables, in which results will be considered significant at P<0.05. Furthermore, two sided log rank test will be used to compare the Survival Curves obtained through analysis of overall survival (OS) Those pocedures will be executed in order to establish and evaluate its statistical relevance to the clinical trial in accordance to its objectives and purposes.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
What are the tasks expected to be accomplished by the student?
TASK 1 and 2: RNA and DNA extraction, high throughput sequencing (HTS) technologies such as Whole-Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) to detect somatic variants occurring at exome level as well as splicing variants, to identify chromosomal translocations/fusion genes, and to produce gene expression profiles. In the Sixth Task a pilot clinical study will translate this knowledge into rationally targeted therapy in aCML (atypical Chronic Myeloid Leukemia) patients: visiting aCML patients. Writing an informal final report
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Approximately 1 seminar per week about hematology (language: English)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a poster
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic Knowledge of Italian is preferable
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Pre-Medical students from the American-British system
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