Investigating the Haematopoietic Stem Cell Origin of Mature Lymphoid Malignancies

The role of cancer cells with stem cell properties in disease progression and resistance to treatment is controversial and heavily researched. While their
existence was shown for certain malignancies, the extent, acquisition, and maintenance of stemness properties remain to be elucidated. Key questions
are when and how differentiation and dedifferentiation occur, and which mutations are acquired at which state of differentiation. The project will focus
on Hairy Cell Leukaemia, a lymphoid malignancy characterized by abnormal differentiated B cells. However, the disease is almost universally
associated with activating BRAF mutations, which are found not only in differentiated cells but also in the haematopoietic stem cell. This makes Hairy
Cell Leukemia an extremely interesting model to study the role and maintenance of stem cells during disease progression. Unpublished genomic
analysis from the Hodson lab, combined with a small number of published exome studies has led us to hypothesize that BRAF mutations synergize
with mutations in cell cycle genes or RNA-binding proteins that themselves control the expression of cell cycle regulators. This project will test how
these mutational combinations subvert normal haematopoiesis to promote the development of lymphoid malignancy.