Équipe 11 - Modélisation des mécanismes de transformation et de résistance dans la leucémie.

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Team 11 - Modeling transformation and resistance in leukemia.

Équipe 11 – Modélisation des mécanismes de transformation et de résistance dans la leucémie.

Our team’s research seeks to understand how malignant transformation of normal tissue arises, with a special interest in the hematopoietic system. Hematopoietic malignancies such as leukemias are thought to arise in the stem and progenitor cells that maintain this system, so we are studying the molecular mechanisms that regulate the functions of these cells. Our work also analyzes the impact of a variety of factors (genetic, epigenetic, etc.) on the propensity of hematopoietic stem and progenitor cells to initiate disease. We are also interested in defining the genetic and molecular mechanisms that contribute to resistance to treatment of leukemia. We specialize in the development and characterization of novel genetic models to study these events using both in vitro and in vivo approaches. Notably, our team members established and manage the CRISP’edit platform, which provides consultation and services for CRISPR-mediated genomic targeting.

Keywords

leukemia, hematopoiesis, resistance, CRISPR, aging

News

3 BRIC projects awarded by the AAP RIE (Interdisciplinary and Exploratory Research) of the University of Bordeaux

Research on the Biology and Diseases of Ageing in Bordeaux

Focus of the SBM Department – Philosophy and science article – cancer research

Events

Projects

Development of a CRISPR-based strategy for increasing the sensitivity for the detection of minimal residual disease in chronic myeloid leukemia

Tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein are the standard of care for the treatment of chronic myeloid leukemia, and patient disease is routinely followed by quantitative PCR measurements of the level of BCR-ABL1 transcripts. Clinical studies have evaluated the possibility for patients who display undetectable levels of BCR-ABL1 for at least 2 years to stop taking TKIs. Nevertheless, 50-60% of these patients who stop taking TKIs will relapse. To determine if BCR-ABL1 transcripts that are undetectable by quantitative PCR are actually present in these patients, we are developing novel detection methods with increased sensitivity. In particular, we are evaluating the use of SHERLOCK (Specific High-sensitivity Enzymatic Reporter uLOCKing) technology as a potential diagnostic tool. SHERLOCK is based on the RNA-targeting enzyme Cas13 with crRNA that permit specific targeting and detection of transcripts of BCR-ABL1.

Project members

In vivo functions of normal hematopoietic and leukemic stem cells

website figure

Hematopoietic stem cells can both self-renew and differentiate into the spectrum of hematopoietic cells, and these dual functions ensure hematopoiesis throughout the lifetime of the organism. Nevertheless, a number of hematopoietic defects including an increased frequency of myeloid neoplasms occur with age. These defects are thought to arise, at least in part, within hematopoietic stem cells, but exactly how this occurs is unclear. We have developed a novel transgenic reporter to study the function of hematopoietic stem cells within their native environment, and we are using this system to define the molecular and cellular mechanisms that contribute to the functional decline of hematopoietic stem cells with age and during the development of leukemia.

Project members

Noteworthy publications

Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals.
Sawai CM, Babovic S, Upadhaya S, Knapp DJHF, Lavin Y, Lau CM, Goloborodko A, Feng J, Fujisaki J, Ding L, Mirny LA, Merad M, Eaves CJ, Reizis B
Immunity ; 2016 Sep 20

Kinetics of adult hematopoietic stem cell differentiation in vivo.
Upadhaya S, Sawai CM, Papalexi E, Rashidfarrokhi A, Jang G, Chattopadhyay P, Satija R, Reizis B
The Journal of experimental medicine ; 2018 Nov 05

New genetic tools for the in vivo study of hematopoietic stem cell function.
Upadhaya S, Reizis B, Sawai CM
Experimental hematology ; 2018 May 01

In-vivo differentiation of adult hematopoietic stem cells from a single-cell point of view.
Nazaraliyev A, Richard E, Sawai CM
Current opinion in hematology ; 2020 Jul 01

Intravital Imaging Reveals Motility of Adult Hematopoietic Stem Cells in the Bone Marrow Niche.
Upadhaya S, Krichevsky O, Akhmetzyanova I, Sawai CM, Fooksman DR, Reizis B
Cell stem cell ; 2020 Aug 06

Mechanisms of therapeutic resistance in pediatric leukemias

Leukemia, in particular acute lymphoblastic leukemia, is the most common form of pediatric cancer (30%) with ~1700 new cases occurring in France annually. Nevertheless, 15-20% of patients will relapse following standard chemotherapy, and for relapsed patients, in particular those with T cell acute lymphoblastic leukemia (T-ALL) the prognosis remains poor. Genetic profiling has identified a number of genes such as NOTCH1, CDKN2A/2B and PTEN that are frequently mutated in T-ALL. We are using in vitro and in vivo approaches to dissect the contribution of various genetic mutations on the efficacy of specific types of targeted therapy that could have a potential therapeutic benefit. We are also developing additional projects based on other pediatric hematologic cancers.

Project members

Stéphane DUCASSOU (Responsable)

Streamlined Geriatric and Oncological evaluation based on IC Technology for holistic patient-oriented healthcare management for older multimorbid patients

Population is aging and the number of complex multimorbid patients to manage will increase sharply. Disease-centred approach is not appropriate to manage these patients. Change to a patient-centred approach will simplify care pathways, secure management and treatment decision making and decrease healthcare costs. It will be a real breakthrough for daily practice with multiple impacts that must be quantified. GERONTE multimorbid patient-centred system proposes: 1) Coordination of management by a patient-tailored, interdisciplinary health professional consortium (HPC), including hospital- and home-based professionals, with a case manager; 2) Timely registration of symptoms and patient-reported outcomes at home through a web-based app for anticipation of avoidable adverse events; 3) Proposal of self-management guidelines according to intrinsic capacity evaluation by geriatrician for patient-driven improvement of independent living; 4) Structured collection of data from electronic health record into a dashboard made available to HPC members as well as patient and caregiver, thanks to its capacity to securely interoperate with all electronic health records including software managing medical data. The whole approach will be co-designed with patients, informal care givers and health professionals. Cancer is an excellent model to develop this approach in multimorbid patients because it is frequent and commonly associated with other morbidities in older patients but also because of its major impact on patients’ general status and coexistent diseases. Cancer already benefits from a multidisciplinary management model that GERONTE will enhance, strengthening exchange of holistic data, role of primary care and case management. GERONTE will also provide new country-specific guidelines and best practices for implementation across Europe and for improved management of older multimorbid patients including improved quality of life and independent living at decreased costs.

Project members

Pierre SOUBEYRAN (Responsable)

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Team’s noteworthy publications

Stem cell decoupling underlies impaired lymphoid development during aging.
Jang G, Contreras Castillo S, Esteva E, Upadhaya S, Feng J, Adams NM, Richard E, Awatramani R, Sawai CM, Reizis B
Proceedings of the National Academy of Sciences of the United States of America ; 2023 May 30

In-vivo differentiation of adult hematopoietic stem cells from a single-cell point of view.
Nazaraliyev A, Richard E, Sawai CM
Current opinion in hematology ; 2020 Jul 01

Specific High-Sensitivity Enzymatic Reporter UnLOCKing-Mediated Detection of Oncogenic BCR::ABL1 and EGFR Rearrangements.
Cullot G, Amintas S, Karembé L, Prouzet-Mauléon V, Rébillard J, Boureau L, Cappellen D, Bedel A, Moreau-Gaudry F, Dulucq S, Dabernat S, Turcq B
The CRISPR journal ; 2023 Apr 01

Novel analytical methods to interpret large sequencing data from small sample sizes.
Lichou F, Orazio S, Dulucq S, Etienne G, Longy M, Hubert C, Groppi A, Monnereau A, Mahon FX, Turcq B
Human genomics ; 2019 Aug 30

Advances in Geriatric Oncology: Exploring Practical Ways to Optimize Treatment in Older Patients with Cancer.
Paillaud E, Hamaker ME, Soubeyran P
Cancers ; 2022 Aug 26