AML: A novel therapeutic target to overcome chemotherapy resistance
Chemotherapy: the standard of care for acute myeloid leukemia
Chemotherapy remains the standard of care for acute myeloid leukemia (AML), a blood cancer that affects approximately 3,500 people each year in France.
Although around 70% of patients initially respond to treatment, 50–70% subsequently relapse due to the persistence of leukemia cells that are resistant to chemotherapy.
The biological mechanisms underlying this chemoresistance remain poorly understood and represent one of the major barriers to achieving durable remission and cure in patients with AML.
Research teams led by Alexandre Puissant and Camille Lobry (Saint-Louis Research Institute, Inserm U1342, Université Paris Cité), Inserm researchers and members of the Leukemia Institute, an Institut Hospitalo-Universitaire (IHU), based at Saint-Louis Hospital (AP-HP), have identified a novel molecular network involved in resistance to chemotherapy.
Their findings, published in Science Translational Medicine on July 8, 2026, uncover a new therapeutic vulnerability linked to the regulation of messenger RNA (mRNA) splicing. The study identifies a molecular pathway, designated the PAK1–CLK1/4–SRRM1 network, as a promising therapeutic target to prevent relapse following chemotherapy.
« Resistance to chemotherapy arises from adaptive mechanisms such as RNA splicing, a process involved in the maturation of messenger RNAs (mRNAs) that enables protein production. Dysregulation of RNA splicing can contribute to disease progression and is associated with poor clinical outcomes.»
Camille Lobry
A splicing network driving chemotherapy resistance
To understand how leukemia cells evade chemotherapy, the researchers analyzed residual leukemia cells persisting after treatment in vivo. By combining multi-omics and functional approaches, they show that chemotherapy-resistant leukemia cells display profound dysregulation of RNA splicing.
The authors identified a network of splicing-related proteins, designated the PAK1–CLK1/4–SRRM1 network, whose activity is markedly increased and which represents a specific vulnerability of resistant leukemia cells.
The researchers also identified a PAK1 variant detected specifically in a subset of patients at relapse and likely to promote resistance to chemotherapy.
These findings highlight the central role of this splicing network in the progression of acute myeloid leukemia.
A new therapeutic strategy to prevent relapse
The study shows that combined inhibition of PAK1 and CLK1/4 corrects splicing abnormalities and preferentially targets chemotherapy-resistant leukemia cells.
By demonstrating the central role of RNA splicing dysregulation in chemotherapy resistance, this study paves the way for the development of new therapeutic strategies combining PAK1 and CLK1/4 inhibitors with standard treatments for acute myeloid leukemia to prevent relapse.
« By simultaneously targeting multiple key components of this molecular network, we are able to restore the sensitivity of leukemia cells to chemotherapy, thereby opening up a new therapeutic avenue to prevent relapse.»
Alexandre Puissant
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