DNA interstrand bridges (ICL) are particularly toxic lesions which covalently link the two DNA strands, blocking the essential cellular processes of DNA replication and transcription.

As ICL particularly affects dividing cells, many ICL-inducing drugs (cisplatin, melphalan, psoralens) are used in chemotherapy. However, excessive exposure to ICL increases the risk of developing treatment-related secondary leukemias .

On the other hand, an intrinsic defect in ICL repair characterizes patients with Fanconi disease, a rare genetic syndrome combining bone marrow aplasia and a predisposition to cancer.

It is in these different contexts that we aim to better understand ICL repair mechanisms and how repair defects lead to pathologies .

Our strategy is based on new molecules synthesized to detect lesions in cells and monitor their repair. In collaboration with chemists, our team has developed a detectable version of melphalan, an alkylating agent that induces ICL.

Our research focuses on the development of various applications for click-melphalan and other new molecules.

Breast cancer is the most common malignancy in women worldwide, accounting for around 25% of all new cases of cancer in women.

Despite this high incidence, the mortality rate is relatively low (15%), mainly due to early diagnosis and the increasing use of adjuvant therapy.

Adjuvant chemotherapy for breast cancer includes the incorporation of taxol (paclitaxel and docetaxel) into anthracycline- and alkylating agent-based treatments. These strategies have considerably improved survival rates, but have also increased the number of treatment-related cases of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

We are currently characterizing the role of the FAN1 protein in the resistance of breast cancer to chemotherapy.

UFMylation is a post-translational modification by UFM1, a small protein belonging to the Ubiquitin family. Murine models have demonstrated its indispensable role in erythroid and nervous system development.

UFMylation is also essential for the survival of acute myeloid leukemia cell models. Although its major functions are involved inendoplasmic reticulum (ER) homeostasis and ER-associated translation, this pathway also plays a key role in maintaining genome stability.

We are continuing our research to identify new substrates modified by UFM1 and better understand its role in the response to DNA damage and the maintenance of genome stability.

Aging and obesity are risk factors for the development of hematological malignancies such as acute myeloid leukemia (AML). Both factors are associated with adipocyte dysfunctions that lead to metabolic and cardiovascular pathologies.

Within the bone marrow, medullary adipose tissue (BMAT), made up of adipocytes and pre-adipocytes, accounts for 45-60% of total marrow volume and around 10% of total adipose tissue in adults.

Anemia is a condition characterized by a lack of erythrocytes, affecting a quarter of the world's population. While most studies focus on iron-deficiency anemia, around 40-50% of anemias are not due to iron deficiency.

These anemias can be the main symptom of rare congenital diseases such as Diamond-Blackfan anemia, β-thalassemia or Fanconi anemia. They are a group of hereditary diseases affecting the bone marrow and resulting in dysfunctional erythrocyte production.

Inherited hemoglobin disorders are classified into two groups:

• Structural disorders of hemoglobin (e.g. sickle cell anemia)
• Disorders related to globin production (thalassemia)

Treatments vary according to the severity of the anemia: from small molecules stimulating red blood cell production, to blood transfusions and bone marrow transplants. However, these treatments are limited in effectiveness and can have serious side effects.

β-Thalassemia is an inherited blood disorder caused by abnormalities in hemoglobin β-chain synthesis. This leads to an accumulation of progenitor cells in the erythroid lineage and inefficient erythropoiesis.

This project will provide a proof of concept in a mouse model of β-thalassemia, which could eventually be applied to other congenital anemias.