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Thematic 2

Thematic 2

The Mammary and Leukemic Oncogenesis group works on the comprehension, follow-up and treatment of chronic myeloid leukemia, T-cell acute lymphoblastic leukemia, and breast cancer (specifically molecular apocrine and familial breast cancers).

Chronic myeloid leukemia is a malignancy that derives from bone marrow stem cells that display a genetic abnormality, the reciprocal translocation t(9;22)(q34;q11) that generates the fusion gene BCR-ABL1. The tyrosine-kinase activity of BCR-ABL1 activates signaling pathways driving proliferation, inhibits apoptosis, and interferes with the genome stability of cells belonging to the myeloid lineage. This disease is a model for understanding the mechanisms of oncogenesis, the design of rational therapeutic strategies (the TKI: tyrosine-kinase inhibitors), the demonstration of the remarkable efficacy of these targeted therapies, but also for the study of resistance and relapse mechanisms that both rely on a shared characteristic of several cancers: the resistance of cancer stem cells to pharmacological treatments. Our team conducts and participates in clinical research programs aimed at improving the current treatments (new generations of TKI, other molecules), and we were the first to demonstrate the feasibility of TKI discontinuation in patients who responded optimally (1). In order to improve patient follow-up, we are currently developing an alternative method for the quantification of BCR-ABL1 mRNA (using a CRISPR-based SHERLOCK approach), and searching for genetic markers (polymorphisms) associated with TKI response quality (either partial or complete) and with resistance to treatment, observed in 10-20% of the patients (2). Another program is evaluating a potential role for the autonomous nervous system in the resistance of leukemic stem cells found in the bone marrow.

Another research project concerns pediatric leukemias (3), notably T-cell acute lymphoblastic leukemia (T-ALL), characterized by poor prognosis. Among the genes commonly mutated in T-ALL are CDKN2A, CDKN2B, and PTEN. We are currently evaluating the impact of CKD4/6 inhibitors alone or in combination with drugs targeting the PI3K/AKT/mTOR pathway, with the aim of blocking signaling downstream of these mutations. We use in vitro approaches with cell lines and establish patient-derived xenograft models for both in vivo and ex vivo studies.

Our team discovered a sub-type of triple-negative breast cancers (TNBC) characterized by the expression of the androgen receptor. Promising clinical trials using androgen receptor antagonists are ongoing regarding these molecular apocrine tumors (4). Nevertheless, we are continuing our research to better understand the biological foundations of this disease and discover new therapeutic targets. One of the main tools used in these studies is the development of 3D cell culture models, in which the genetic abnormalities found in tumors are reproduced.

Another project based on medical genetics focuses on the identification and the diagnostic/prognostic value of mutations of genes implicated in mammary tumorigenesis (5) : PTEN, BRCA2, ATM, among others.

In recent years, our team has been very active in the development of methods using CRISPR/Cas9 technology, which led to the creation of a dedicated core facility (www.tbmcore.u-bordeaux.fr/crispedit/).

1 – Etienne G, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol 2017 (35): 298-305
2 – Lichou F, et al. Novel analytical methods to interpret large sequencing data from small sample sizes. Hum Genomics 2019 (13): 41
3 – Ducassou et al. MYB-GATA1 fusion promotes basophilic leukaemia: involvement of interleukin-33 and nerve growth factor receptors. J Pathol 2017 (242):347-357
4 – Bonnefoi H, et al. Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes. Br J Cancer 2019 (120): 913-921
5 – Bubien V, et al. Combined tumor genomic profiling and exome sequencing in a breast cancer family implicates ATM in tumorigenesis: A proof of principle study. Genes Chromosomes Cancer 2017 (56):788-799