Disentangling the metabolism in Richter Transformation

Master’s Thesis Project Proposal

Title: Disentangling the metabolism in Richter Transformation (RT)

Background

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world and typically follows an indolent clinical course. A subset of patients, about 5 to 10 percent, develop Richter transformation (RT). This condition presents as an aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL), and is associated with rapid progression and poor prognosis. RT cells differ markedly from CLL cells: they are often two to three times larger, form solid lymphomas rather than circulating leukemias, show higher proliferative activity, and display substantial genetic instability. Despite these major differences, the mechanisms that drive the transformation are still largely unknown.

One area in which RT cells diverge significantly from CLL cells is cellular metabolism, which is increasingly recognized as a key contributor to transformation and therapeutic resistance. RT metabolism is characterized by increased metabolic demand, mitochondrial rewiring, elevated oxidative phosphorylation (OXPHOS), enhanced tricarboxylic acid (TCA) cycle flux, and high production of reactive oxygen species (ROS). However, the underlying cause of this metabolic shift is not well understood, and both the mechanism driving it and the advantage it provides to the cancer remain largely unknown.

Project Description

In this project, we aim to characterize the altered metabolism in RT and determine its role in the transformation process, with the ultimate goal of identifying metabolic interventions that could either reverse the transformation or exploit metabolic vulnerabilities to eliminate RT cells. Our work will focus on an RT cell line, compared against a DLBCL cell line and additional B-cell lines serving as controls. The project is partly exploratory, with experimental directions adjusted based on prior results. Most of the work will be performed in the wet lab, complemented by computational analyses such as differential expression profiling and metabolic modeling.

Methods

Examples of potential activities include:

• Cell culture

• RNA sequencing and downstream analysis

• Measurement of ATP/ADP and NAD⁺/NADH ratios

• Assessment of mitochondrial membrane potential

• Evaluation of nucleotide availability and imbalances

• Viability assays under metabolic perturbations

• Measurements of metabolite uptake rates

• Metabolic modeling

Most of the time will be spent in the wet lab. The computational components are optional and can be carried out by other members of the lab if needed.

Expected Outcomes

This project will provide insight into the rewired metabolism of RT, and we hope to reach an understanding of what drives its altered metabolism and identify potential interventions that can either reverse the transformation or selectively kill the RT cells.

Requirements

• Basic wet lab experience

• Computational skills are meriting, but not necessary

• An interest to learn about cancer metabolism and leukemia/lymphoma biology.

Supervision

The project will be carried out in the Tumor Immunology (TIMM) Lab at Sahlgrenska Center for Cancer Research, University of Gothenburg, under the supervision of Johan Gustafsson (main supervisor) and Elin Bernson (co-supervisor).

Project timeline

The project duration is 1 year. We aim to start the project as soon as possible, but the start date is a bit flexible.

Contact

Applications (or questions) should be sent to johan.gustafsson.2@gu.se.