Dominance of an &lt;i&gt;UBA1&lt;/i&gt; mutant clone over a &lt;i&gt;CALR&lt;/i&gt; mutant clone: from essential thrombocytemia to VEXAS.

Hage-Sleiman, Mehdi; Lalevée, Sébastien; Guermouche, Hélène; Favale, Fabrizia; Chaquin, Michaël; Battistella, Maxime; Bouaziz, Jean‐David; Bagot, M.; Delhommeau, François; Cordoliani, F.; Hirsch, Pierre

doi:10.3324/haematol.2021.279418

Cited by 21 publications

(16 citation statements)

References 12 publications

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“…In these male patients of myeloid malignancies, we observed three different scenarios: (i) Lv [20] human UBA1 variants as the main clone, (ii) UBA1 variants as subclonal events in combination with known leukemic driver events, and (iii) UBA1 variants as a secondary major driver event following treatment. Scenario (iii) has been described in one case report of a patient initially diagnosed with ET treated with hydroxyurea subsequently developing MDS after acquiring a UBA1 variant [34].…”

Section: Discussionmentioning

confidence: 95%

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

et al. 2023

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UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1non-M41) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1non-M41 putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.

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Section: Discussionmentioning

confidence: 95%

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

et al. 2023

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“…Based on the available evidence, antineoplastic agents such as this drug may induce tumors even when used in therapeutic dosages, as they are cytotoxic and genotoxic [ 9 ]. To our knowledge, there are only a few patients with MPN and concomitant VEXAS syndrome, and both CALR and JAK2 mutations are now described [ 1 ]. We can speculate that the administration of HU has significance to the second gene mutation, although there is no supporting evidence for this correlation.…”

Section: Discussionmentioning

confidence: 99%

“…There are only a few descriptions of coexistence of myeloproliferative neoplasms (MPNs) in VEXAS syndrome in the literature. We present a case of a male with essential thrombocythemia (ET) that develops symptoms leading to the diagnosis of coexisting VEXAS syndrome [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

VEXAS Syndrome in a Patient with Myeloproliferative Neoplasia

Austestad

Madland

Sandnes

et al. 2023

Case Reports in Hematology

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VEXAS syndrome stands for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome. The syndrome is a combined hematological and rheumatological condition caused by a somatic mutation in the UBA1. There is an association between VEXAS and hematological conditions such as myelodysplastic syndrome (MDS), monoclonal gammopathies of uncertain conditions (MGUS), multiple myeloma (MM), and monoclonal B-cell lymphoproliferative conditions. There are not many descriptions of patients having VEXAS in combination with myeloproliferative neoplasm (MPN). With this article, we want to present a case history of a man in his sixties with a JAK2V617F mutated essential thrombocythemia (ET) developing VEXAS syndrome. The inflammatory symptoms occurred three and a half years after the ET diagnosis. He started to experience symptoms of autoinflammation and an overall worsening of his health, and blood work showed high inflammatory markers, leading to repeated hospitalizations. His major complaint was stiffness and pain, and high dosages of prednisolone were necessary to obtain pain relief. He subsequently developed anemia and significantly variable levels of thrombocytes, which previously were at a steady level. To evaluate his ET, we made a bone marrow smear demonstrating vacuolated myeloid and erythroid cells. Having VEXAS syndrome in mind, genetic testing identifying the UBA1 gene mutation was performed, thus confirming our suspicion. The work-up with myeloid panel on his bone marrow identified genetic mutation in the DNMT3 too. After developing VEXAS syndrome, he experienced thromboembolic events with both cerebral infarction and pulmonary embolism. Thromboembolic events are also common in JAK2 mutated patients, but in his case, they presented first after VEXAS had developed. Throughout the course of his condition, several attempts with prednisolone tapering and steroid sparing drugs were tried. He could not get pain relief unless the combination of medications included a relatively high dose of prednisolone. Currently, the patient uses prednisolone, anagrelide, and ruxolitinib, with partial remission and fewer hospitalizations and more stabilized hemoglobin and thrombocytes.

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“…Our patient has CALR (57% allele frequency), ZRSR2 (89% allele frequency) and UBA1 mutations. CALR mutation acts as a driver mutation for MPN and a decrease in allele frequency is observed with treatment 23. The differentials of cytoplasmic vacuoles include copper deficiency, alcohol abuse, zinc and heavy metal toxicity 11.…”

Section: Discussionmentioning

confidence: 99%

VEXAS syndrome with progression of MDS to MDS/MPN overlap syndrome

et al. 2022

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VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome is a novel inflammatory syndrome that was first described in December 2020. Patients with VEXAS syndrome have a somatic mutation in the UBA1 gene, inflammatory conditions and usually haematological conditions. Haematological conditions reported in patients with VEXAS syndrome include myelodysplastic syndrome (MDS), clonal cytopenia of undetermined significance, plasma cell neoplasm including multiple myeloma/monoclonal gammopathy of undetermined significance, haemophagocytic lymphohistiocytosis and monoclonal B-cell lymphocytosis. Here we describe a patient with VEXAS syndrome who had a progression of MDS to MDS/myeloproliferative neoplasm overlap syndrome. The ocular findings so far reported in these patients include episcleritis, uveitis, blepharitis and orbital cellulitis. Here we report retinal detachment as a clinical feature of VEXAS syndrome. This finding has a significant implication in patient management as it warrants higher vigilance for this sight-threatening complication.

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Dominance of an <i>UBA1</i> mutant clone over a <i>CALR</i> mutant clone: from essential thrombocytemia to VEXAS.

Abstract: Not available.

Cited by 21 publications

References 12 publications

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

VEXAS Syndrome in a Patient with Myeloproliferative Neoplasia

VEXAS syndrome with progression of MDS to MDS/MPN overlap syndrome

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