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SUMMARYAcquired mutations in theUBA1gene, occurring in myeloid cells and resulting in expression of a catalytically impaired isoform of the enzyme E1, were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). The precise physiological and clinical impact of these mutations remains poorly defined.Here, we studied a unique prospective cohort of individuals with severe autoinflammatory disease with (VEXAS) or without (VEXAS-like)UBA1somatic mutations and compared with low-risk myelodysplastic syndromes (MDS) and aged gender-matched healthy controls. We performed an integrated immune analysis including multiparameter phenotyping of peripheral blood leukocytes, cytokines profiling, bulk and single-cell gene expression analyses and skin tissue imaging mass cytometry.Focusing on myeloid cells, we show that monocytes fromUBA1-mutated individuals were quantitatively and qualitatively impaired and displayed features of exhaustion with aberrant expression of chemokine receptors. Within affected tissues, pathological skin biopsies from VEXAS patients showed an abundant enrichment of CD16+CD163+monocytes adjacent to blood vessels and M1 macrophages, possibly promoting local inflammation in part through STAT3 activation. In peripheral blood from VEXAS patients, we identified a significant increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirmed the role of circulating cells in the IL-1β and IL-18 dysregulation in VEXAS patients and revealed a significant enrichment of TNF-α and NFκB signaling pathways that could mediate cell death and inflammation. Single-cell analysis confirmed the inflammatory state of monocytes from VEXAS patients and allowed us to identify specific molecular pathways that could explain monocytopenia, especially the activation of PANoptosis and a deficiency in the TYROBP/DAP12 axis and β-catenin signaling pathway. Together, these findings on monocytes from patients withUBA1mutations provide important insights into the molecular mechanisms involving the mature myeloid commitment in VEXAS syndrome and suggest that the control of the undescribed inflammasome activation and PANoptosis could be novel therapeutic targets in this condition.GRAPHICAL ABSTRACT

Introduction La neuropathie amyloide AL, une cause rare d’atteinte nerveuse peripherique, associe generalement une atteinte distale symetrique et une dysautonomie. Nous rapportons une presentation atypique, essentiellement caracterisee par une plexopathie unilaterale. Observation Une patiente de 74 ans consulte en hematologie pour alteration de l’etat general, polyadenopathie et bicytopenie. L’anamnese revele des paresthesies du territoire C8 gauche depuis 2 ans. L’immunofixation montre un pic monoclonal IgM lambda et la biopsie osteomedullaire pose le diagnostic de maladie de Waldenstrom. La patiente est traitee par alkylant puis anti-CD20, permettant la regression de l’infiltrat medullaire. Au cours de la meme annee apparait neanmoins un deficit moteur des territoires C5 a T1 gauches ainsi qu’une paralysie du nerf III gauche. Les IRM cerebrale et orbitaire sont normales. L’EMG met en evidence une baisse des amplitudes sensitives dans le territoire plexique gauche et des traces neurogenes dans les muscles correspondants. L’IRM du rachis cervical et l’etude du LCR sont normaux. L’IRM des plexi brachiaux revele une atteinte bilaterale, plurisegmentaire et confluente, d’allure inflammatoire. La PET-TDM est normale. La patiente est traitee par immunoglobulines IV. La poursuite de la degradation clinique et neurophysiologique fait pratiquer une biopsie des glandes salivaires, laquelle revele des depots d’amylose AL, et une biopsie du nerf radial, qui confirme le diagnostic de neuropathie amyloide. Discussion La plexopathie est une presentation rare d’atteinte neurologique amyloide, pouvant initialement etre consideree comme une neuropathie inflammatoire. La poursuite de l’aggravation sous immunoglobulines IV doit faire reconsiderer le diagnostic. Une fois le diagnostic de neuropathie amyloide AL etabli, le traitement repose sur la prise en charge de la pathologie hematologique sous-jacente, meme s’il ne permet que rarement la stabilisation clinique. Conclusion La neuropathie amyloide AL est une affection rare, dont la presentation peut s’averer trompeuse. Elle peut etre revelee par une plexopathie monomelique et comporter l’atteinte de paires crâniennes. Conclusion Image 1 : Depots Rouge Congo sur biopsie nerveuse, Dr Maisonobe.

Sustained Leukemia-Free State and Molecular Response to Sorafenib in a Patient With Chronic Myelomonocytic Leukemia in Transformation Driven by Homozygous FLT3-ITD Malignant Hematopoiesis Olivier Kosmider, Nicolas Chapuis, Sophie Kaltenbach, Romain Coriat, Pascaline Boudou Rouquette, Lise Willems, Virginie Chesnais, Isabelle Radford-Weiss, Valerie Bardet, Patrick Mayeux, Jerome Tamburini, Michaela Fontenay, Didier Bouscary

Clostridium difficile (C. difficile) infection was observed in 13% of recipients after hematopoietic stem cell transplantation (HSCT), mainly in the first month posttransplantation. Risk factors were cord blood as the source of stem cells, acute graft-versus-host disease (GVHD), and total body irradiation (TBI). No association was found with an increased risk of mortality. The purpose of this study was to evaluate the incidence, risk factors, and outcome of C. difficile infection (CDI) after HSCT. We conducted a single-center, retrospective, cohort study on all patients who received an allogeneic HSCT from January 2004 to December 2007. All patients with diarrhea in the first year after HSCT were tested for the presence of C. difficile in stools. Among the 407 assessable patients, 53 presented at least 1 CDI in the first year post-HSCT. The total incidence rate was 5.6 cases of CDI per 10,000 patient-days. Fifty percent of cases were diagnosed in the first month after HSCT, and 95% occurred during the first 6 months. Fewer than 5% of patients with CDI had severe diarrhea and severe complications were never observed. TBI in the conditioning regimen, cord blood as the source of stem cells, and acute graft-versus-host disease (aGVHD) were independently associated with CDI. Six patients (11%) had a recurrence of CDI. Four patients required second-line treatment with vancomycin. With a median follow-up of 22 months, the 2-year overall survival rates were similar between patients who presented a CDI and those who did not. CDI was observed in approximately 13% of recipients after HSCT, mainly in the first month posttransplantation and was associated with CB, aGVHD, and TBI. CDI was not associated either with severe complications or with an increased risk of mortality in this large cohort of patients.