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Case Report
macrocytic anemia persisted, in association with a bio- logical inflammatory syndrome with elevated C-reactive protein, and cutaneous lesions that led to a VEXAS hypothesis. Sanger sequencing identified an UBA1 vari- ant with a high allele burden (p.Met41Leu, c.121A>C [NM_153280.3]) (Figure 2B). Cytoplasmic vacuoles in erythroid and granulocytic precursors were also observed (Figure 1B). A retrospectively UBA1 mutation screening of the initial BM sample and skin biopsy detected the same variant at a lower allele burden, revealing the clonal sweep from the CALR mutated “ET clone” to the UBA1 “VEXAS” clone (Figure 2C). A treatment by ruxolitinib, the efficacy of which has been reported in VEXAS puta- tively due to its anti-inflammatory properties rather than a direct effect on the UBA1 mutated clone, was started and is currently ongoing with good improvement of cuta- neous lesions.2 Hematopoietic stem cell transplantation was not considered due to the age of over 75 years at the time of VEXAS diagnosis.
A recent publication reports the newly described
VEXAS syndrome, linked to somatic mutations in UBA1.1
Our case illustrates similar clinical manifestations with
regard to the described entity, but the patient did not
exhibit all the key clinical features like fever, pulmonary
involvement, or polychondritis. This case suggests that
UBA1 mutations can be associated to a diversity of clini-
cal presentations and that the clinical spectrum of UBA1
related disease has to be refined. Other teams already
described the frequent incomplete clinical presentation,
and other not initially described involvement
(vasculitis-like aspect or other) has also been report- ed.2,3,5,6
Sweet’s syndrome was present in eight of 25 (32%) participants from the first series of VEXAS syndrome.1 There are two forms of Sweet’s syndrome: neutrophilic and histiocytoid.7,8 The histiocytoid subset, character- ized by a dermal infiltration of immature myeloid cells with histiocytoid morphology, is associated with myelodysplastic syndromes in 24-31% of the cases.7 Some authors think that myelodysplasia cutis can be con- firmed when the same cytogenetic abnormalities are found in the skin and BM of patients with histiocytoid Sweet’s syndrome without leukemia, as in our patient.4 To our knowledge, this is the first report of myelodysplasia cutis associated with UBA1 mutations.
In our patient, we describe a progressive clonal replace- ment of a preexisting CALR-mutated ET clone, and illus- trate the parallel clonal and phenotypic dynamics of two distinct driver-associated diseases. These results, thus demonstrate a clonal implication of different clones with a shared DNMT3A-mutated founder clone (Figure 2C). We assumed the association of DNMT3A and CALR mutations in the BM to be responsible for the initial ET. Then the association of the DNMT3A mutation, UBA1 mutation, and monosomy 7, occurring in a subclone dis- tinct from the DNMT3A and CALR mutant subclone, was associated with a skin tropism, with a minority of cells harboring monosomy 7 in the BM. Finally, the CALR clone was outcompeted by the UBA1 clone, which result- ed in the clinical remission of the ET, and in the develop- ment of the VEXAS phenotype associating anemia, vac- uolated myeloid precursors and systemic inflammation.
CALR mutations are strong driver mutations in myelo- proliferative neoplasms. A decrease in allele burden can be observed during therapy such as interferon-α,8 or in around half of the cases of secondary acute myeloid leukemia related to myeloproliferative neoplasms.9 In the present observation, clonal dominance conferred by the UBA1 mutation seems to be a major event during clonal
evolution. This suggests that UBA1 mutations may pro- vide a powerful selective advantage, able to overcome a CALR mutated clone. This might be due to a putative effect of UBA1 on the mutated hematopoietic stem cell proliferation and self-renewal, or might be in link with major changes induced by the autoinflammatory microenvironment that probably plays a role in shaping the clonal architecture, and might result in a selective advantage of the UBA1 clone over others.
In this observation, the role of hydroxyurea or thalido- mide in clonal evolution cannot be excluded. It remains however unlikely, as the effects of hydroxyurea on CALR clones are often very limited, and the effects of thalido- mide are known to be limited in thromboembolism cases. Moreover, expansion of preexisting clones after lenalinomide therapy, which is closely related to thalido- mide or incidence of second malignancy after lenalino- mide have not been clearly demonstrated.10–12
In conclusion, we describe the clonal dynamics of a CALR mutated subclone associated with ET, crushed by an UBA1 mutated subclone associated with myelodyspla- sia cutis and VEXAS, developing on a preexisting DNMT3A clonal hematopoiesis. This suggests somatic mutations of UBA1 can be associated with other muta- tions, and can be a secondary major driver event in clonal evolution. Common clinical features between VEXAS and hematological neoplasms with inflammatory mani- festations could lead to a misdiagnosis. Extensive screen- ing for UBA1 mutation is required to determine the real prevalence of VEXAS among patients with atypical pres- entation of myeloid neoplasms.
Mehdi Hage-Sleiman,1 Sophie Lalevée,2 Hélène Guermouche,1 Fabrizia Favale,1 Michael Chaquin,1
Maxime Battistella,3,4 Jean-David Bouaziz,1,4
Martine Bagot,2,4 François Delhommeau,1 Florence Cordoliani2 and Pierre Hirsch1
1Sorbonne Université, INSERM, Centre de Recherche Saint- Antoine, AP-HP, Hôpital Saint-Antoine, Service d’Hématologie Biologique; 2Dermatology Department, Saint-Louis Hospital, AP-HP; 3Pathology Department, Saint-Louis Hospital, AP-HP and 4Université de Paris, Paris, France
Correspondence: PIERRE HIRSCH - pierre.hirsch@aphp.fr doi:10.3324/haematol.2021.279418
Received: June 11, 2021.
Accepted: July 21, 2021.
Pre-published: July 29, 2021.
Disclosures: no conflicts of interest to disclose.
Contributions: MHS and PH performed molecular analyses and wrote the manuscript; SL, FC MB and JDB provided dermatologic data; MB performed histological analyses; FF performed molecular analyses; MC and FD performed cytological analyses; HG performed cytogenetic and FISH analyses. All authors contributed to manuscript writing.
Funding: this work was supported by SiRIC CURAMUS (INCA-DGOS-Inserm_12560).
References
1. Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383(27):2628-2638
2.Bourbon E, Heiblig M, Gerfaud-Valentin M, et al. Therapeutic options in Vexas syndrome: insights from a retrospective series. Blood. 2021;137(26):3682-3684.
3. Oganesyan A, Jachiet V, Chasset F, et al. VEXAS syndrome: still
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