Impaired cytotoxic function and exhausted phenotype of natural killer cells in VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder caused by acquired somatic UBA1 mutations in hematopoietic stem cells, affecting peripheral myeloid and natural killer (NK) cells. Given the high rate of severe infections observed in VEXAS patients, we hypothesized that NK cell dysfunction contributes to this increased susceptibility. We conducted a comprehensive immune characterization of peripheral NK cells in patients with VEXAS (n=40), patients with autoinflammatory diseases without UBA1 mutations (n=22), and elderly gender-matched healthy controls (HCs) (n=16).

JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms.

JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib's impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations. Single-cell DNA sequencing combined with ex vivo treatment of RAS mutated CD34 primary patient cells, demonstrates that ruxolitinib induces RAS clonal selection both in a JAK/STAT wild-type and hyper-activated context.

Modeling mesenchymal stromal cell support to hematopoiesis within a novel 3D artificial marrow organoid system.

The human bone marrow (BM) microenvironment involves hematopoietic and non-hematopoietic cell subsets organized in a complex architecture. Tremendous efforts have been made to model it in order to analyze normal or pathological hematopoiesis and its stromal counterpart. Herein, we report an original, fully-human in vitro 3D model of the BM microenvironment dedicated to study interactions taking place between mesenchymal stromal cells (MSC) and hematopoietic stem and progenitor cells (HSPC) during the hematopoietic differentiation.

[VEXAS Syndrome].

VEXAS SYNDROME. VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described autoinflammatory syndrome, mostly affecting men above 50 years, caused by somatic mutation in the X-linked UBA1 gene. Patients present a broad spectrum of inflammatory manifestations (fever, neutrophilic dermatosis, chondritis, pulmonary infiltrates, ocular inflammation, venous thrombosis) with hematological involvement (macrocytic anemia, thrombocytopenia, vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow) which are responsible for significant morbidity and mortality.

Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from the FRENVEX group.

VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is a severe monogenic disorder caused by somatic UBA1 mutations, characterized by inflammation, cytopenias and frequent association with myelodysplastic neoplasms (MDS). Steroid dependence is common, and targeted therapies have demonstrated limited efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS but data remain limited.

Prognostic significance of monocytic-like phenotype in patients with AML treated with venetoclax and azacytidine.

The prognostic impact of monocytic differentiation in patients with acute myeloid leukemia (AML) receiving venetoclax (Ven) and azacitidine (Aza) remains unclear. In a prospective cohort of 86 newly diagnosed patients with AML treated with Ven-Aza, we used multiparametric flow cytometry (MFC) to define monoblasts as AML blasts coexpressing ≥2 monocytic markers (CD4, CD36, and CD64) per European LeukemiaNet (ELN) guidelines. Patients with higher monoblasts/CD45+ proportions had lower complete response rates (odds ratio, 0.

Inflammatory Signatures in VEXAS Syndrome, Myelodysplasia Cutis, and Sweet Syndrome.

Importance: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a monogenic disease caused by UBA1 somatic variants in hematopoietic progenitor cells, mostly involving adult men. It is associated with inflammatory-related symptoms, frequently involving the skin and hematological disorders. Recently described myelodysplasia cutis (MDS-cutis) is a cutaneous manifestation of myelodysplasia in which clonal myelodysplastic cells infiltrate the skin.

A non-conditioned bone marrow transplantation mouse model to study clonal hematopoiesis and myeloid malignancies.

Clonal hematopoiesis of indeterminate potential (CHIP) is a condition where blood or bone marrow cells carry mutations associated with hematological malignancies. Individuals with CHIP have an increased risk of developing hematological malignancies, atherosclerotic cardiovascular disease, and all-cause mortality. Bone marrow transplantation (BMT) of cells carrying CHIP mutations into irradiated mice are useful procedures to investigate the dynamics of clonal expansion and potential therapeutic strategies, but myeloablative conditioning can induce confounding effects.

Understanding Myelodysplasia and Inflammation Through the Lense of VEXAS Syndrome: A Review.

VEXAS syndrome, a monogenic X-linked disorder resulting from mutations in the UBA1 gene, has emerged as a key model for unraveling the links between systemic inflammatory or autoimmune diseases (SIAD) and myelodysplastic syndromes (MD). This syndrome is characterized by the presence of vacuoles, X-linked inheritance, autoinflammation, and somatic mutation patterns, highlighting a unique intersection between genetic and immunological dysregulation. Apart from VEXAS, 10% to 30% of individuals diagnosed with MDS exhibit SIAD phenotypes, a significant increase compared to the 5% incidence in the general population.

MOSAIC: An Artificial Intelligence-Based Framework for Multimodal Analysis, Classification, and Personalized Prognostic Assessment in Rare Cancers.

Purpose: Rare cancers constitute over 20% of human neoplasms, often affecting patients with unmet medical needs. The development of effective classification and prognostication systems is crucial to improve the decision-making process and drive innovative treatment strategies. We have created and implemented MOSAIC, an artificial intelligence (AI)-based framework designed for multimodal analysis, classification, and personalized prognostic assessment in rare cancers.

[Dysimmune manifestations associated with myelodysplastic neoplasms and chronic myelomonocytic leukaemias].

Systemic inflammatory or autoimmune diseases (SIAD) are observed in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML), with a broad clinical spectrum including asymptomatic biological abnormalities, isolated inflammatory clinical manifestations (recurrent fever, arthralgia, neutrophilic dermatoses…) or identified systemic diseases (giant cell arteritis, recurrent polychondritis…). Recent advances in molecular biology have shed new light on the pathophysiological mechanisms that link inflammatory manifestations and myeloid hemopathies, particularly in VEXAS syndrome following the identification of somatic mutations in the UBA1 gene, or in neutrophilic dermatoses with the concept of myelodysplasia cutis. Although the presence of SIAD does not seem to affect overall survival or the risk of transformation into acute myeloid leukemia, their treatment remains a challenge given the frequent high level of corticosteroid dependence as well as the poor efficacy and tolerance (cytopenias, infections) of conventional immunosuppressive agents.

Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders, representing high risk of progression to acute myeloid leukaemia, and frequently associated to somatic mutations, notably in the epigenetic regulator TET2. Natural Killer (NK) cells play a role in the anti-leukemic immune response via their cytolytic activity. Here we show that patients with MDS clones harbouring mutations in the TET2 gene are characterised by phenotypic defects in their circulating NK cells.