Guillaume P. Andrieu

Kudos to all the authors and collaborators involved in this long effort over the years! @inem-necker.bsky.social @hopitalnecker.bsky.social @institut-leucemie.bsky.social

LEF1 Intragenic Deletion Induces a Dominant-Negative isoform and unveils a Wnt/β3-Catenin Vulnerability in T-ALL Key Points. LEF1 intragenic deletion is the most frequent LEF1 alteration in T-ALL and leads to a dominant-negative isoform.LEF1 intragenic deletion confer

Happy to share our study published in @bloodjournal.bsky.social

🧬✂️🛑
We report that intragenic deletions of LEF1 generate a dominant-negative isoform and confer a targetable dependence on the Wnt/β-catenin pathway in T-ALL

Full story 👉: doi.org/10.1182/bloo...

Congratulations Jan! This is well deserved and honors your deep commitment to hematology and hematologists.

A fantastic program, insightful discussions, and exciting perspectives coming from the @helloeacr.bsky.social EACR Conference ‘Persister Cells’ on how to better identify, characterize and target drug-tolerant persister cells to leverage the treatment of bacterial infections and cancers.

🧐 PI3King on leukemia: Targeting PI3K and related vulnerabilities is a promising avenue in the treatment of leukemia. Recent studies by Andy Lane’s and Alex Puissant’s labs provided strong rationale for exploiting PI3Kgamma dependency in AML, paving the way for new PI3K-directed therapies.

🤔 An insight on L-ASNases: The benefit of L-ASNases in the treatment of ALL is indisputable. Among L-ASNases, Erwinase has a direct glutaminase activity that we exploit to treat PI3K-driven leukemia, over other forms such as Kidrolase that do not synergize with mTOR inhibition.

🔜 Future perspectives: These promising results require confirmation. This is the scope of ALL-TARGET (NCT05832125), an initiative combining precision medicine and an observatory to evaluate therapeutic proposals based on mutational profile and signaling pathways alterations.

💉 Back to the clinic: With the active collaboration of our clinicians, we were able to treat five patients suffering from aggressive refractory T-ALL/LL. Complete response was obtained in all the cases, allowing HSCT for three of them.

🎯 The targeted strategy: To exploit this singularity, we combined mTOR inhibitor temsirolimus that limits glucose consumption by the blasts, with an L-asparaginase Erwinase that has a direct glutaminase activity to obtain a robust anti-leukemic effect on PI3K-driven T-ALL/T-LL.

🔥 The metabolic trait: By integrative transcriptome and metabolome profiling, we revealed a singular metabolic polarization of PI3K-driven leukemias that extensively rely on glutamine mobilization to the TCA cycle to cope with glucose limitation.

NGS-based stratification refines the risk stratification in T-ALL and identifies a very-high-risk subgroup of patients Key PointsNGS-based stratification refines risk classification in T-ALL.NGS classifier combined with MRD and WBC identifies a group of patients with a very

🩺 The clinical evidence: As in solid tumors, leukemias with alterations of the PI3K signaling pathways have a poor prognosis. This is particularly true in T-ALL, an aggressive form of acute leukemia. For a recent update, please see Simonin et al 2024.

ashpublications.org/blood/articl...

A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer - Nature Communications Deregulation of the Phosphoinositide 3-kinase (PI3K) pathway is associated with metabolic flexibility leading to cancer poor prognosis. Here, the authors show that targeting both glutamine degradation...

📣Thrilled to share our recent study presenting a clinical-grade targeted therapy to exploit a metabolic vulnerability of PI3K-driven leukemia published in @naturecomms.bsky.social

🧵Key insights detailed below.

www.nature.com/articles/s41...