To identify the genetic driver mutations and evolutionary histories over the disease course, Dr. Nadeu’s lab first sequenced the whole genome of 54 longitudinal samples covering up to 19 years of disease course in 19 cases of chronic lymphocytic leukemia (CLL) developing Richter’s transformation (RT). They then performed single-cell DNA sequencing using the Tapestri Platform and the 32-gene CLL Catalog Panel from Mission Bio on 16 longitudinal samples of four cases to validate these evolutionary histories of RT, and to track early driver mutations over the disease course. Dr. Nadeau will discuss how singlecell DNA sequencing allowed high-sensitivity detection of driver mutations that bulk next generation sequencing didn’t call, identifying minute subclones at the time of CLL diagnosis which were dormant for six to 19 years until rapid expansion at transformation. He will also overview the findings from the study that suggest that CLL evolution to RT is driven by pre-existing subclones generated before diagnosis and that early intervention to eradicate the dormant RT subclones may prevent the future development of this lethal complication of CLL, uncovering potential therapeutic targets for RT.
