By using a high-throughput CRISPR-based technique, his team can now map thousands of genes simultaneously to reveal the mechanisms behind treatment-resistant acute myeloid leukemia.
Molecular screening at Saint-Louis Hospital
For decades, researchers struggled to identify the specific genetic mutations driving various blood cancers. While the discovery of gene fusion in promyelocytic leukemia in the 1990s led to significant breakthroughs in treatment, other forms of the disease, such as acute myeloid leukemia, proved far more complex. The variety of genetic anomalies made it nearly impossible to target the disease effectively, as cells often developed new resistance mechanisms when one pathway was blocked.
Puissant’s work, which earned him the Cino and Simone Del Duca Foundation cancer research prize, focuses on overcoming these persistent resistance barriers. His laboratory utilizes a method formulated during his postdoctoral work in Boston and perfected in Paris to conduct comprehensive genetic screening. Instead of testing genes one by one, the team now uses virus-delivered CRISPR-Cas9 systems to deactivate thousands of genes at once in living mice models. This allows researchers to isolate which genetic “bolts” cause the biological circuit of the cancer to fail.
RNA splicing and cellular camouflage
The research, conducted in collaboration with Camille Lobry and a team of international specialists, has provided new insight into how tumor cells survive chemotherapy. The team found that leukemic cells can alter how they read their genetic instructions without changing their actual DNA sequence. By manipulating the molecular networks responsible for RNA splicing—a critical step in protein production—the cells effectively adopt a form of “camouflage” that allows them to evade the effects of standard treatments.
This mechanism was detailed in a study published in Science Translational Medicine in July 2026. By combining specific chemical inhibitors, the researchers successfully deactivated these protective networks in mouse models, significantly slowing the rate of relapse.
Repurposing existing treatments
The laboratory’s focus on functional genomics has also led to the identification of potential new uses for existing drugs. In 2022, Puissant’s team identified that leukemic cells are highly dependent on the SLC7A11 cysteine transporter to multiply. This finding led to the study of sulfasalazine, an older medication already on the market for inflammatory conditions, as a potential way to block this transport mechanism and inhibit tumor growth.
An clinical trial for the repurposing of this drug is currently recruiting patients at Saint-Louis Hospital. This research model, which integrates fundamental biological discovery with translation into animal testing and clinical recruitment, was highlighted by the Cino and Simone Del Duca Foundation as a significant advancement in the understanding and management of acute myeloid leukemia.
The next phase of this research involves monitoring the ongoing clinical trials at Saint-Louis Hospital to determine the efficacy of the repositioned sulfasalazine treatment in human patients.
