Biology subjects

Gruden, E.

Publications and source records attributed to Gruden, E..

3 recordsLinked to original sources

bioRxiv2026

Enhanced environmental complexity worsens experimental colitis and dysregulates microbiota-gut-brain axis signalling in female mice

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by colonic inflammation and bloody diarrhoea. Accumulating evidence suggests that UC not only affects the intestinal tract, but also distant organs including the brain. Environmental factors are key determinants of the disease course, yet the impact and potential disease modifying effects of living environment complexity on microbiota-gut-brain axis signalling during colitis remain unclear. To address this gap, we investigated how enhanced environmental complexity (EC) affects the disease course and gut-brain axis signalling during experimental colitis in mice. Our results show that EC exacerbates dextran sulphate sodium (DSS)-induced colitis in female mice, but not in male mice, as evidenced by greater weight loss and higher disease activity. Immune cell profiling across the gut-brain axis reveals strong effects of DSS treatment on colonic, circulating and brain immune cell populations and a restriction of central nervous system (CNS) T cell infiltration due to EC. In addition, female EC/DSS mice have higher circulating corticosterone levels than controls indicating chronic stress. Metabolomics across the gut-brain axis revealed that EC exacerbates colitis-induced metabolite perturbations in plasma, brain tissue, brain interstitial and cerebrospinal fluid. Notably, microbiota-derived metabolites, including deoxycholic acid and trimethylamine-N-oxide (TMAO), are increased in EC/DSS mice, concordant with EC-associated microbiome changes and anxiety-like behaviour. Overall, this study indicates that EC worsens experimental colitis in female mice and directs microbiota-gut-brain axis signalling during colitis towards a less favourable state. From a translational perspective, this study highlights the importance of environmental factors for a sex-specific disease course of UC and associated neurobehavioral comorbidities. HighlightsO_LIEnhanced environmental complexity (EC) exacerbates experimental colitis C_LIO_LIColitis and EC have compartment-specific effects on immune cells C_LIO_LIEC augments colitis-induced metabolic shifts in plasma, brain and CSF C_LIO_LIMicrobiota-derived metabolites are important players for the effects of EC C_LI

neuroscience↗

bioRxiv2026

EZH2 inactivation drives MAPK-dependent vulnerability to MEK inhibition in RAS-mutant CMML

Chronic myelomonocytic leukemia (CMML) is a heterogeneous hematologic malignancy with limited therapeutic options. Although RAS and RAS-modifying mutations (RASmut) are common and associated with poor prognosis, targeting RAS signaling has shown limited clinical success. Here, we define co-occurrence of RASmut and EZH2 inactivation (EZH2inact) as a distinct molecular subgroup of CMML characterized by aggressive disease biology. Mechanistically, RASmutEZH2inact drives selective MAPK/ERK hyperactivation in mature myeloid cells and hematopoietic stem and progenitor compartments. Transcriptomic analysis of a large independent myeloid neoplasm cohort (Beat-AML) further supports this finding, demonstrating selective activation of gene signatures of MAPK/ERK activation in RASmutEZH2inact cases. Functionally, this signaling activation promotes proliferation and myelomonocytic differentiation in human and murine models. Therapeutically, this MAPK/ERK upregulation confers increased sensitivity to MEK inhibition (MEKi). In a murine RasmutEzh2inact-driven CMML model, MEKi suppresses MAPK/ERK activity and reduces leukemic burden by impairing proliferation and myelomonocytic differentiation without inducing cell death. In primary human CMML samples ex vivo, MEKi shows stronger anti-proliferative effects in RASmutEZH2inact specimens compared with RASmut samples. Drug-sensitivity data from the Beat-AML cohort further supported this. Ultimately, these findings were confirmed in a patient-derived xenograft model, where MEKi reduced the leukemic burden by selectively inhibiting the proliferation of transplanted human RASmutEZH2inact leukemic cells. In summary, our data define RASmutEZH2inact CMML as a clinically relevant subgroup with selective MAPK/ERK hyperactivation and increased sensitivity to MEKi. They provide a mechanistic explanation for the limited efficacy of MEK inhibitors in unselected CMML and support molecularly guided use of MEK-targeted therapy in this patient population.

molecular biology↗

bioRxiv2026

RAS-mutant clones drive extramedullary acute myeloid leukemia

Extramedullary acute myeloid leukemia (eAML) represents a clinically challenging manifestation of acute myeloid leukemia (AML), but its molecular drivers remain poorly defined. We performed targeted sequencing in 85 eAML biopsies, representing one of the largest molecular analyses of eAML to date. We detected mutations in RAS or RAS-modifying genes (RASMUT; NRAS, KRAS, PTPN11, CBL, and NF1) in 41% of cases, representing a significant enrichment compared to bone marrow (BM) samples of more than 1300 AML patients not selected for eAML. Analysis of paired eAML and BM specimens revealed expansion and/or de-novo appearance of RASMUT clones at the extramedullary site. Functional studies using primary murine leukemia cells and CRISPR/Cas9-engineered isogenic human leukemia cell lines demonstrated that RASMUT increase the migration and invasion of leukemic cells compared to RAS-wildtype controls. Consistently, RASMUT cells showed increased infiltration into the chorioallantoic membrane of chicken embryos and demonstrated enhanced extramedullary growth after injection into immunocompromised mice. RNA sequencing revealed increased expression of junctional adhesion molecule-like (JAML) and activation of PI3K/AKT signaling in RASMUT cells. JAML silencing and pharmacologic AKT inhibition reversed the RASMUT-driven effects on leukemic cell migration, demonstrating a causal role of the JAML-PI3K/AKT axis in RASMUT-driven eAML formation. In conclusion, these findings delineate the molecular landscape of extramedullary AML and show that RASMUT are enriched within this AML subform. They further demonstrate that RASMUT actively contribute to leukemic tissue infiltration through activation of a RASMUT-JAML-PI3K/AKT axis, highlighting AKT signaling as a potential therapeutic vulnerability in RASMUT-associated eAML.

cancer biology↗