bims-actimu 2025-05-25 papers

Issue of 2025–05–25
three papers selected by
Elodie Busch, University of Strasbourg

Br J Haematol. 2025 May 21.

Efficacy and safety of romiplostim and eltrombopag in management of thrombocytopenia in Wiskott-Aldrich syndrome patients.

Anna Ogneva, Yulia Rodina, Dmitry Pershin, Kirill Voronin, Anastasia Prozvetkina, Alexey Maschan, Galina Novichkova, Nikolay Grachev, Anna Shcherbina.

Wiskott-Aldrich syndrome (WAS) is a life-threatening inborn error of immunity associated with bleeding risk due to profound thrombocytopenia. We previously demonstrated that romiplostim is effective for thrombocytopenia treatment in 60% of WAS patients. In this prospective trial, 28 WAS patients (aged 0-17 years) were treated with thrombopoietin receptor agonists (TPO-RAs) to evaluate the comparative efficacy and safety of romiplostim versus eltrombopag and to assess the benefit of switching these molecules in individual subjects. We demonstrate that both drugs are effective, with the probability of achieving an overall platelet response (complete response-platelet count of 100 × 109/L or more and partial response-platelet count increase of 30 × 109/L or higher above baseline) of 73% for romiplostim and 43% for eltrombopag. Switching to an alternative TPO-RA allowed the achievement of a complete platelet response in 33% of patients after switching to eltrombopag and in 43% after romiplostim initiation. The cumulative efficacy of TPO-RAs, taking into account alternative therapy, was 87%. There was a grade 2 adverse event (AE) and a severe grade 4 AE related to eltrombopag-reversible acute liver failure associated with metabolic acidosis and encephalopathy. TPO-RAs proved to be an effective treatment for WAS patients waiting for stem cell transplantation or opting for a conservative treatment.

Keywords: Wiskott–Aldrich syndrome; bleeding; eltrombopag; romiplostim; thrombopoietin receptor agonist

DOI: https://doi.org/10.1111/bjh.20182

Commun Biol. 2025 May 21. 8(1): 776

Negative cooperativity regulates ligand activation of DIAPH1 and other diaphanous related formins.

G G Theophall, A Premo, S Reverdatto, E Omojowolo, P Nazarian, D S Burz, R Ramasamy, A M Schmidt, A Shekhtman.

DIAPH1 is a member of the family of Diaphanous Related Formins (DRFs) implicated in cell migration and cytokinesis. DRFs are maintained in an autoinhibited state by the intramolecular association between diaphanous inhibitory (DID) and diaphanous autoregulatory (DAD) domains. Actin polymerization requires the binding of activated RhoA to the GTPase binding domain (GBD) of DIAPH1 and the dissociation of DAD. In the presence of excess RhoA, actin polymerization is only partially activated. Using monomeric domain constructs of DIAPH1, the sequential binding affinities of RhoA and DAD to GBD-DID were characterized. Binding of RhoA and DAD were negatively cooperative requiring a 100-fold greater concentration of DAD to achieve saturation when RhoA binding site was occupied. The unimolecular architecture of full length DIAPH1 establishes an effective concentration of DAD in the micromolar range, which is 100-fold larger than the intrinsic affinity of DAD for DID. The effective concentration is large enough to maintain DIAPH1 autoinhibition, yet small enough to permit partial activation of DIAPH1 after RhoA binding. By exploiting negative cooperativity, DIAPH1 maintains a reserve of inactivated molecules enabling gradual responses to cellular processes that require prolonged and sustained regulation. The proposed mechanism is extended to other DIAPH1 activating ligands and broadly applicable to all DRFs.

DOI: https://doi.org/10.1038/s42003-025-08222-5

J Exp Med. 2025 Aug 04. pii: e20250339. [Epub ahead of print]222(8):

A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.

Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, Sophie Panigot, Daiki Mori, Liaoxun Lu, Guillaume Voisinne, Carine Vilarnau Wolek, Marielle Mello, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Frédéric Fiore, Romain Roncagalli, Yinming Liang, Marie Malissen, Bernard Malissen.

Naive T cell activation requires both TCR and CD28 signals. The CARMIL2 cytosolic protein enables CD28-dependent activation of the NF-κB transcription factor via its ability to link CD28 to the CARD11 adaptor protein. Here, we developed mice expressing a mutation named Carmil2QE and mimicking a mutation found in human T cell malignancies. Naive T cells from Carmil2QE mice contained preformed CARMIL2QE-CARD11 complexes in numbers comparable to those assembling in wild-type T cells after CD28 engagement. Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly induced most of the functions that normally result from CD28 engagement in a manner that remains antigen-dependent. In turn, tumor-specific T cells expressing Carmil2QE do not require CD28 engagement and thereby escape to both PD-1 and CTLA-4 inhibition. In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those triggered by CD28 and exploited them to induce potent solid tumor-specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors.

DOI: https://doi.org/10.1084/jem.20250339