1. Introduction and background
Dissecting Roles of Dynein Light Chain 1 towards The Novel Therapy for Lymphomas Lingli Li, PhD candidate, Year 3, Department of Medicine/
School of Medicine, Dentistry and Health sciences, University of Melbourne /SVI @lilly9612
Introduction and background
B cell lymphomas are blood cancers arise from B cell development defects .
Cell circle and apoptosis are critical steps for maintaining cell numbers during normal B cell development.
B-lymphocytes (B cells) guard our health and are responsible for humoral immunity by producing antibodies required.
Dynein Light Chain 1
Dynein light chain 1 (DYNLL1) is part of the cytoplasmic dynein motor complex
Structural Role:
DYNLL1
Mark P Dodding and Michael Way The EMBO Journal (2011)
DYNLL1 binds to multiple proteins regulates protein expression in cell cycle, apoptosis etc
Gene Regulator:
Jurado, S, J Biol Chem. 2012
B cells are continuously generated from precursors in the bone marrow, development and differentiation are mainly regulated by BCR (B cell receptor) and Pre-BCR (Pre B cell receptor) signals.
More than half of the aggressive types of NHL are incurable with poor three-year survival (30-50%) and severe side effects under current treatments. Target therapy becomes the focus of search for effective treatment of lymphomas.

2. Important steps for early B cell development
B cell Tumorigenesis
Ulf Klein & Riccardo Dalla-Favera. 2008
Important steps for early B cell development
Modified from Hardy, R et al, Annul Review
Immunology 19, (2001)
in Heierhorst lab, SVI
Conditional Deletion of Dynll1 using Cre Recombination
Research Strategy
Heierhorst lab data SVI

3. Results 1: DYNLL1 in early B cell development
Reduction of Splenic B cells to 12%
B cells in Periphery Blood and in Spleen
Decres
Cell cycle Profile shows in Pre B cells: Cell division slow down G1 C’
B cells in blood
Ctrl
Del
B cells
B cells in spleen
Deletion of Dynll1:
Huge reduction of B cells in periphery blood and in spleen
Deletion of Dynll1
Decrease of the cycling fraction C’ fraction of Pre B, fewer dividing cells]
More cells pause at G1 phase before entering to cell cycling.
B Cells
Pre B cells
Snapshot of B Cell Fractions in Bone Marrow
Immature B
Decres
Apoptosis analysis showed that in Immature B cells: Cell death Up
Cell Death
Deletion of Dynll1 in Bone marrow
Big Loss of Pre B cells( C’ + D )
Huge loss of immature B cells (E)
Deletion of Dynll1
Increase of apoptosis rate, immature B cells die fast before leave bone marrow.
B Cells
References
References
LeBien, T. W. & Tedder, T. F. B , Blood 112, (2008).
Hardy, R et al, Annul Review Immunology 19, (20001)
Kuppers, R. Nat Rev Cancer 5, (2005).
Jurado, S.,et al J Exp Med 209, (2012).
Adams, J. M et al, Nature 318, (1985).
Jurado, S. et al, J Biol Chem 287, (2012).
Rapali, P et al, FEBS J 278, (2011).
Puthalakath, H et al Mol Cell 3, (1999).
Bouillet, P et al, Science 286, (1999).
Hobeika, E et al, Proc Natl Acad Sci U S A 103, (2006).
LeBien, T. W. & Tedder, T. F. B , Blood 112, (2008).
Hardy, R et al, Annul Review Immunology 19, (20001)
Kuppers, R. Nat Rev Cancer 5, (2005).
Jurado, S.,et al J Exp Med 209, (2012).
Adams, J. M et al, Nature 318, (1985).
Jurado, S. et al, J Biol Chem 287, (2012).
Rapali, P et al, FEBS J 278, (2011).
Puthalakath, H et al Mol Cell 3, (1999).
Bouillet, P et al, Science 286, (1999).
Hobeika, E et al, Proc Natl Acad Sci U S A 103, (2006).

4. Results 2: DYNLL1 in Lymphomagenesis
Dramatic reduction of immature B in Pre Tumor Mice
Survival Analysis of Leukemic Mice
Ctrl
Del
Double Mut
Wong, D et al, Cell Rep. 16;14(6): (2016).
Deletion of Dynll1 in Myc driven pre tumor mice:
Huge reduction of Immature B and circulating B cell numbers
Immature B cell fraction in mice
Deletion of Dynll1 in tumor mice, protects mice from tumor formation:
Significantly increase the life span of tumor mice
Significant fewer mice develop tumors
Fewer mice develop lymphomas
There is significant increase in life span when deleted Dynll1.

5. References References Conclusions
Dynll1 is essential for early B cell development in the bone marrow:
regulates apoptosis processes in immature B cells
facilitates cell cycle entry at the Pre B cell stage
The significant protection of Dynll1-deleted mice from lymphoma formation indicates that DYNLL1 might be a novel target for therapeutic strategies to treat B cell lymphomas.
Acknowledgements:
Supervisory and Advisory committee: A/P Jörg Heierhorst, A/Prof Jock Campbell, Dr Ora Obernard, A/ Prof Carl Walkley, Dr Meaghan Wall
Bio Resources Centre in St Vincent’s Hospital
Funding: APA University of Melbourne Scholarship and Leukaemia foundation PhD Scholarship
Host institute: SVI and University of Melbourne
References:
Adams, J. M et al, Nature 318, (1985).
Bouillet, P et al, Science 286, (1999).
Dupunt, T et al, Oncotarget. 19;7(3): (2016).
Hardy, R et al, Annul Review Immunology 19, (2001).
Hobeika, E et al, Proc Natl Acad Sci U S A 103, (2006).
Jurado, S.,et al J Exp Med 209, (2012).
Jurado, S. et al, J Biol Chem 287, (2012).
Kuppers, R. Nat Rev Cancer 5, (2005).
LeBien, T. W. & Tedder, T. F. B , Blood 112, (2008).
Mark P Dodding and Michael Way, The EMBO Journal (2011).
Rapali, P et al, FEBS J 278, (2011).
Puthalakath, H et al Mol Cell 3, (1999).
Ulf Klein & Riccardo Dalla-Favera. Nature Reviews Immunology 8, (2008).
Roberts AW et al, N Engl J Med28;374(4): (2016).
Xiao Q, et al, Int J Biol Sci 12(9): (2016).
Wong, D et al, Cell Rep. 16;14(6): (2016).
All experimental results used in this poster have been generated using Heierhorst lab resources in SVI by the author, some are yet to be published.
References
References
LeBien, T. W. & Tedder, T. F. B , Blood 112, (2008).
Hardy, R et al, Annul Review Immunology 19, (20001)
Kuppers, R. Nat Rev Cancer 5, (2005).
Jurado, S.,et al J Exp Med 209, (2012).
Adams, J. M et al, Nature 318, (1985).
Jurado, S. et al, J Biol Chem 287, (2012).
Rapali, P et al, FEBS J 278, (2011).
Puthalakath, H et al Mol Cell 3, (1999).
Bouillet, P et al, Science 286, (1999).
Hobeika, E et al, Proc Natl Acad Sci U S A 103, (2006).
LeBien, T. W. & Tedder, T. F. B , Blood 112, (2008).
Hardy, R et al, Annul Review Immunology 19, (20001)
Kuppers, R. Nat Rev Cancer 5, (2005).
Jurado, S.,et al J Exp Med 209, (2012).
Adams, J. M et al, Nature 318, (1985).
Jurado, S. et al, J Biol Chem 287, (2012).
Rapali, P et al, FEBS J 278, (2011).
Puthalakath, H et al Mol Cell 3, (1999).
Bouillet, P et al, Science 286, (1999).
Hobeika, E et al, Proc Natl Acad Sci U S A 103, (2006).