Lecture will be held in English

Hosted by

Marek Mráz

About the lecture

Dissecting the interplay between genetic lesions and the tumor microenvironment in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a common B cell malignancy characterized by the progressive accumulation of autoreactive B lymphocytes that are driven to expand by a complex interplay of genetic lesions and signals that the leukemic cells receive from the tumor microenvironment. Recent large-scale next generation sequencing studies have shown that the genetic landscape in CLL is highly heterogeneous, with point mutations or copy number alterations detected in more than 200 putative CLL driver genes. However, with few exceptions, the majority of the genetic lesions are relatively infrequent and their role during leukemia development, progression, transformation, and their impact on response to treatment are still unknown. Moreover, in vivo models to study how these genetic lesions cooperate between themselves and how they cooperate with signals from the tumor microenvironment are largely lacking. To facilitate such studies, we recently developed a CRISPR/Cas9-editing approach that allows for simultaneous introduction of mutations in multiple putative CLL driver genes in normal or leukemic murine B cells as well as genetic disruption of intracellular pathways that propagate microenvironmental signals in murine CLL cells or human Richter Syndrome patient-derived xenografts. The genetically modified cells are then transplanted in recipient mice to investigate how individual genetic lesions or microenvironmental signals affect the growth of the leukemic cells in vivo and how they influence the response to treatment with novel targeted therapies. We have used this procedure in two recent studies to show that recurrent genetic lesions in TP53 and the cell cycle inhibitors CDKN2A and CDKN2B cooperate with B cell receptor signals during Richter Transformation (Chakraborty S et al, Blood 2021) and to define the microenvironmental signals that are most relevant for the growth of xenografted patient-derived Richter Syndrome cells in vivo (Martines C et al, Blood 2022). The results from these and ongoing studies investigating additional genetic lesions will be presented in this talk.

Registration for lunch with the speaker /for Ph.D. students/

The sponsored lunch usually takes place in the Campus River restaurant. Please meet the speaker and other students at 12:45 at the reception desk at the main entrance (building B22, see the map below).