PhD Scientific Days 2025

EUniWell I.

Oncogenic HRAS and NRAS drive functional and morphological remodeling of neutrophils in zebrafish AML models, providing a platform for in vivo drug screening

Előadó neve

Jiménez Blaya Alba

Előadó munkahelye

Universidad de Murcia (UMU), Departamento de Biología Celular e Histología, Murcia, España

Előadó e-mail címe

alba.jimenezb@um.es

Az előadás címe

Oncogenic HRAS and NRAS drive functional and morphological remodeling of neutrophils in zebrafish AML models, providing a platform for in vivo drug screening

Szerző(k) neve és munkahelye

Jiménez Blaya, Alba^1,2, Martinez Navarro, Francisco Juan², Cabello Villalba, Cynthia María², de Oliveira, Sofia³, García Castillo, Jesús², Alcaráz Pérez, Francisca², Mulero Méndez, Victoriano Francisco^1,2, Cayuela Fuentes, María Luisa²

1: Universidad de Murcia (UMU), Departamento de Biología Celular e Histología, Murcia, España
2: Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB-Arrixaca), Murcia, España
3: Albert Einstein College of Medicine, Department of Developmental and Molecular Biology, New York, USA

Bemutatás módja

Szóbeli

Szekció

EUniWell I.

Language of the presentation

English

Összefoglaló szövege

Acute myeloid leukemia (AML) is a complex and aggressive malignancy characterized by the clonal proliferation of immature myeloid cells. To study the cellular mechanisms underlying AML in vivo, we developed two zebrafish models expressing constitutively active Ras isoforms specifically in neutrophils: Tg(lyz:mVENUS-NRAS_Q61L) and Tg(mpx:GAL4;UAS:eGFPHRAS_G12V). These models enable real-time visualization of neutrophils and reproduce key features of leukemic transformation.
In both lines, oncogenic Ras expression led to a marked expansion and systemic dispersal of neutrophils, contrasting with the localized distribution observed in healthy controls.
Time-lapse confocal imaging revealed that transformed neutrophils not only proliferate excessively but also acquire enhanced motility—moving faster, farther, and more directionally than normal cells. Interestingly, these altered dynamics were restricted to Ras-expressing
neutrophils, underscoring a cell-autonomous effect of the oncogenes.
Morphological analyses further revealed distinct oncogene-specific phenotypes: HRAStransformed neutrophils appeared larger and less spherical than those expressing NRAS, suggesting differential remodeling of cytoskeletal architecture. Despite their hypermotility,
neutrophils in both models exhibited a diminished response to tissue injury. Following tail-fin wounding, their recruitment to the site of inflammation was significantly impaired, indicating that oncogenic signaling uncouples migratory capacity from functional responsiveness.
To assess immune function more directly, we monitored NETosis under basal and PMAstimulated conditions. While stimulation triggered robust NET formation in control neutrophils, this response was substantially blunted in both AML models—particularly in HRAS-expressing cells—suggesting that Ras activation compromises a key antimicrobial mechanism.
Finally, we tested the therapeutic potential of targeting the Ras pathway. Treatment with the MEK inhibitor Cobimetinibor the Ras mimetic Rigosertib effectively reduced neutrophil expansion and partially restored normal tissue distribution in vivo.
Together, these findings establish two complementary zebrafish models that recapitulate essential features of Ras-driven AML, reveal distinct functional consequences of HRAS versus NRAS activation, and provide a powerful platform for mechanistic studies and drug
screening in a live vertebrate system.

University

University of Murcia

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

1611

Start

11:00

End

11:15