Pre-leukemic B cell repertoire alterations in patients with familial chronic lymphocytic leukemia: looking for evidence of a genetically-inherited defect in tolerance induction

Informations projet

REPTOL

N° de convention de subvention: 794075

DOI

10.3030/794075

Projet clôturé

Date de signature de la CE 13 Avril 2018

Date de début 1 Avril 2019

Date de fin 31 Mars 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 180 277,20

Contribution de l’UE

€ 180 277,20

Coordonné par

UNIVERSITA DEGLI STUDI DI GENOVA
Italy

Periodic Reporting for period 1 - REPTOL (Pre-leukemic B cell repertoire alterations in patients with familial chronic lymphocytic leukemia: looking for evidence of a genetically-inherited defect in tolerance induction)

Période du rapport: 2019-04-01 au 2021-03-31

Résumé du contexte et des objectifs généraux du projet

Chronic Lymphocytic Leukemia is the most common adult leukemia in the western world and to date is still uncurable. Chronic Lymphocytic Leukemia (CLL) affects predominantly people over 55 years old; in many cases patients survive with the disease for years, suffering very low quality of life and with consequent huge healthcare costs. Many aspects of CLL pathogenesis are still unknown, including the origin of the cells, f the mechanisms of early and late leukemogenesis process, and the progression of the disease.

Understanding the CLL pathogenesis can lead the way for new therapeutic approaches, for prevention strategies and for the identification of risk factors which are probably mostly genetically inherited.

The action successfully provided insight into the pathogenesis process of CLL, suggesting an early non-clinical stage characterized by the expansion of several B cell clone with CLL characteristics. Subsequently one of the clones will eventually complete the transformation and became the clinically relevant CLL.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The project aimed to better understand the pathogenesis and progression of Chronic Lymphocytic Leukemia.
The CLL pathogenesis aspect was addressed by studying the Immunoglobulins (antibodies) in healthy donors looking for a signature characteristic of Chronic Lymphocytic Leukemia. For this purpose, we sequenced the antibodies DNA from 2 cohort of donors, characterized by either the cells biopsy from spleen or peripheral blood. B cells were initially separated in different B cell subsets through the identification of molecules present on the cells surface and then the DNA was sequenced. We identified CLL-like antibodies in multiple B cell subsets.

The progression aspect was addressed by studying the leukaemic immunoglobulin evolution in over 60 Chronic Lymphocytic Leukemia patients. We looked at the antibody DNA sequences, specifically looking for variants bearing mutations. The distribution and features of such mutations were used to understand how the leukemic clone change during the disease course, and its potential clinical implication.
Overall, the results of the action indicates that:
• CLL does not originate from discrete B cell population
• CLL origin involves a pre-clinical stage presenting the expansion of several B cells with CLL-like antibodies
• Fully transformed leukemic clones present a dysregulated process mutating its DNA
The results have been disseminated through publications in Open Access Peer Review journals.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

This study suggested that, unlikely what previously proposed, Chronic Lymphocytic Leukemia does not derive from a single B cell population but likely involves several B cell compartments depending on the antibody characteristics.
The antibody sequence is subject to an ongoing mutation process, and the resulting complexity correlates to the clinical outcome.
Our findings then contribute to further understand the origin and biological evolution of the disease.
In the long term, the project results will impact early diagnosis, prevention, and targeted therapies of CLL. The understanding of the molecular and cellular basis of CLL ontogeny will allow to identify subjects that will eventually develop CLL and block the mechanisms on the basis of early CLL leukemogenic process.

Example of intraclonal diversification os a CLL clone