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A Glimpse into the Genetics of CLL

A Glimpse into the Genetics of CLL. By Lara Makewita Ph.D. Student. About Me and Our Group!. Ph.D. student from the University of Southampton at the Faculty of Medicine A large CLL research group of which there are 7 principal investigators leading research

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A Glimpse into the Genetics of CLL

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  1. A Glimpse into the Genetics of CLL By Lara Makewita Ph.D. Student

  2. About Me and Our Group! • Ph.D. student from the University of Southampton at the Faculty of Medicine • A large CLL research group of which there are 7 principal investigators leading research • My supervisor  Professor Jonathan Strefford • Our research group  focus on CLL (epi)genomics

  3. Introduction • Leukaemia – a word coined in German from the Greek words leukos (white) and haima (blood). • Defined as a cancer of the blood which originates in the bone marrow • Loss of control of normal regulation mechanisms such that too many immature or abnormal white blood cells are made

  4. The Cell • Basic building blocks of all living things  over 37 trillion cells in your body! • Nucleus hosts our hereditary material i.e. DNA

  5. In the Nucleus

  6. In the Nucleus

  7. Cell Cycle • Cells follow the circle of life too! • Extremely important that this cycle is regulated properly for the well being of individuals Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch

  8. Balance is Key Cell Production Cell Death Normal Cells

  9. Balance is Key Cell Production Cell Death Normal Cells

  10. Balance is Key Cell Production Cell Death Leukaemic Cells

  11. Balance is Key Cell Production Cell Death Leukaemic Cells

  12. Balance is Key Cell Production Cell Death Leukaemic Cells

  13. Balance is Key Cell Production Cell Death Leukaemic Cells

  14. Chronic Lymphocytic Leukaemia (CLL) • The most common form of leukaemia in adults in the western world • It arises from B lymphocytes  a type of white blood cell • B lymphocytes are an important part of the immune system  gives the immune system memory to fight against known enemies in the bodies!! • Has a B-cell receptor (BCR) which allows them to recognise molecules or communicate with other cells

  15. B Lymphocyte B-cell receptor B cell Molecule of interest Nucleus

  16. B-cell Development BONE MARROW GERMINAL CENTRE Y Y Y Y Y Y Plasma B cell Naïve CD5+ B cell Y B-cell receptor (BCR) Antigen B-cell development Legend Memory B cell

  17. IG Genes • IG Immunoglobulin genes • A group of genes that help the BCR differentiate to adapt to a particular target • Makes the BCR more specific to a particular stimulus by undergoing several small programmed mutations

  18. J V V V D J C J J D J V V D D D C V J C V D J IG Heavy Chain (IGHV): with D gene segments J J J V V V J J V V C IG Light Chain (IGLV): without D gene segments

  19. C C V V J J C C V V D D J J

  20. C C V V J J C C V V D D J J • These BCRs are found on the cell membrane of B cells • Naïve B cells that have not bound to foreign molecules will not undergo this process C C C C C C

  21. IGHV Genes • IGHV genes code for part of the BCR • Very important for the proper formation of the BCR BUT • CLL cells can arise before or after this adapting process can take place

  22. B-Cell Development BONE MARROW GERMINAL CENTRE Y Y Y Y Y Y Y Y Plasma B cell Naïve CD5+ B cell Y B-cell receptor (BCR) Antigen B-cell development Legend Memory B cell CLL transformation Extremely different clinical outcomes But why? IGHV mutated CLL IGHVunmutated CLL

  23. IGHV Genes • Studies have established a clinico-biological feature of CLL by assessing the mutational status of the IGHVgenes • Mutated IGHV CLL cases, M-CLL (≤98% similarity to the germline IGHV gene) • M-CLL is likely to have derived from memory B cells • UnmutatedIGHV CLL cases, U-CLL (≥98% similarity to the germline IGHV gene) • U-CLL is likely to have stemmed from naïve B cells

  24. B-Cell Development BONE MARROW GERMINAL CENTRE Y Y Y Y Y Y Y Y Plasma B cell Naïve CD5+ B cell Y B-cell receptor (BCR) Antigen B-cell development Legend Memory B cell CLL transformation 100% <98% 99.99 - 98% IGHV mutated CLL IGHVunmutated CLL Percentage Similarity to Germline IGHV

  25. IGHV Genes • U-CLL cases are more likely to follow a more aggressive disease course • M-CLL cases are more likely to follow a more indolent disease course However…nothing is as simple as this in biology…

  26. Deletion Inversion Translocation Insertion Chromosomal Abnormalities 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 4 2 2 2 2 2 2 2 2 2 2 2 2 2 3 2 2 2 2 2 2 6 3 3 3 3 3 2 3 3 3 3 3 3 7 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 Pericentric 4 4 4 4 4 2 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 4 3 7 3 6 6 6 6 6 6 6 6 6 6 Normal 4 Paracentric 4 7 7 7 7 7 7 7 7 7 7 Duplication

  27. Checkpoint Proteins in the Cell Cycle Mitosis Phase 1 Cell Growth • Essential in the cell cycle  prevents the cell cycle from continuing past checkpoints if something is wrong • Important that proteins facilitate these checkpoints • Activates DNA damage repair proteins • Or initiates cell death Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch

  28. Checkpoint Proteins TP53 17 • TP53 gene that codes for the p53 protein • Located on chromosome 17 Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch

  29. Checkpoint Proteins TP53 17 • Mutations in this region can cause the production of a defunct protein Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch

  30. Checkpoint Proteins TP53 17 • Loss in this region will cause no protein production Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch

  31. Checkpoint Proteins ATM • ATM gene that codes for the ATM protein • Located on chromosome 11 Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch 11

  32. Checkpoint Proteins ATM • Mutations in this region can cause the production of a defunct protein Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch 11

  33. Checkpoint Proteins ATM • Loss in this region will cause no protein production Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch 11

  34. Checkpoint Proteins • Faulty proteins are not functional • Checkpoint in cell cycle cannot be enforced • Abnormal cells will be continually produced • TP53 mutations more often seen in del17p CLL patients • ATM mutations more often seen in del11q CLL patients Mitosis Phase 1 Cell Growth Phase 3 Cell Growth Ch Phase 2 Make more DNA!!! Ch

  35. FISH – A Cytogenetic Technique • FISH - Fluorescence In-Situ Hybridisation • Technique used to identify the presence of specific DNA sequences

  36. FISH – A Cytogenetic Technique • Can identify if and which chromosomes have changed e.g. can observe deletions, inversions etc. • Clinicians use this technique to identify these changes and categorise patients to decide the appropriate treatment going forward

  37. A Little About My Research:Epigenetics in CLL

  38. What We know Already • CLL is a B cell cancer • Varied outcomes between patients • Due to various abnormalities in the genes e.g. U-CLL and M-CLL • Due to external factors to DNA that cause changes in gene expression • Looking at the epigenomics of CLL What is she talking about???

  39. Gene Expression

  40. Epigenetics • The study of changes in organisms caused by modifying gene expression rather than the alteration of the DNA sequence itself • External factors that cause the change in the shape of DNA to allow or prevent gene expression. Gene Expression No Gene Expression

  41. Imagine… LIFE

  42. Actors/Actresses Script Epigenetic Director

  43. Epigenetic Mechanism:Chromatin Modelling Gene Expression No Gene Expression Activity Possible

  44. My Work • CLL has several sub-types • Want to improve our understanding of the interactions the surrounding environment of the cell has on the DNA of CLL cells • Identify active genes in stimulated CLL cells using research methods • Potential targets for future therapeutics • Have used methods that can identify these open regions in chromatin in the absence/presence of external stimuli

  45. My Work • Analyse these opening regions using computational tools • Can take some of these regions and validate in the lab for future work in the clinic • Epigenetics will provide some insight to other ways gene regulation occurs in CLL • Will provide other prognostic markers by the means of identifying interacting molecules in the cell environment • Ever-evolving technology and progression in this field, so beneficial for many diseases in the long-run

  46. Acknowledgements • University of Southampton • Professor Jonathan Strefford • Dr Dean Bryant • Dr Jane Gibson • IRIDIS Team - IRIDIS High Performance Computing Facility • Bournemouth Hospital • Professor David Oscier • Dr Renata Walewska • Dr Helen McCarthy • Bournemouth Leukaemia Fund

  47. Thank you for listening!

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