PROJET IMMUNO-CLONE

Characterization of auto-immunity, auto-inflammation and erythropoiesis associated with clonal hematopoiesis

Ce projet est porté par l’Institut IMAGINE – Université Paris Cité – Institut Necker Enfants-Malades – Saint-Antoine Sorbonne Université.

CONTEXT

Clonal hematopoiesis is characterized by the presence of an acquired somatic mutation in hematopoietic cells. The prevalence of these mutations increases with age and are most frequently without clinical significance, and called clonal hematopoiesis of indeterminate potential (CHIP). Some of these somatic mutations (or combination) can induce also secondary autoimmune/autoinflammatory manifestations (SAIDs) associated or not with myeloid neoplasms. We propose to call these entities as “clonal hematopoiesis of immune significance” (CHIS). The recent example of CHIS is the discovery of UBA1 somatic mutation, which allowed to describe the VEXAS syndrome, an autoinflammatory disease from clonal origin associated or not with myelodysplastic syndrome.

Our consortium is a leader (Prof. Mekinian on behalf MINHEMON and French VEXAS group) in the field of SAIDs associated with hematological neoplasms and has set up the first Mondial prospective phase II trial investigating the efficacy of azacytidine in the treatment of SAIDs related with hematological neoplasms. In addition, our consortium is a leader in the field of innate or acquired auto-inflammation among adults in France (Prof. Georgin-Lavialle on behalf CEREMAIA). Furthermore, Prof Georgin-Lavialle and Prof Mekinian are cofounders and head of the French national VEXAS group and database. Finally, Prof. Hermine is the head of the Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutical implications (INSERM U1163, Institut Imagine), where fundamental work in these areas is performed. His areas of expertise will allow us to study the hematological and immunological features observed with SAIDs and particularly related to VEXAS syndrome.

OBJECTIVES

The aims of this project are to :

Characterize the hematological and immunological aspects of MDS/CMML-CHIS (Work Package 1).
Characterize the CHIS in autoinflammatory diseases including familial Mediterranean fever (FMF) and hyperinflammatory gammapathy (HiG) (Work Package 2).
Characterize the CHIS and innate immune cells from the blood and artery lesions in giant cells arteritis (Work Package 3).
Characterized the physiopathology anemia in VEXAS with respect to erythropoiesis and red cells (Wok Package 4).

RESULTS

Work package 1:

MDS-CHIS (N=17): MDS-CHIS patients have higher levels of IL-1β, IL-16 and IL-1RA compared with controls and decrease of TNF-β compared with MDS patients. MDS-CHIS patients have decrease of non-classical monocytes compared with MDS patients. No difference for calprotectin level.
CMML-CHIS (N=16): Exome sequencing: several rare variants described in interferon pathway (TREX1 and IFIH1) and inflammasome (TNFAIP3 and RIPK1). CMML-CHIS patients have higher levels of calprotectin (S100A8/A9 protein) and secretion of cytokines and chemokines involved in innate and adaptive immunity than control CMML patients. CMML-CHIS patients have a higher pDC population and lower HLA-DR expression by classical monocytes.

Work package 2: CHIS in autoinflammatory diseases

CHIS among patients with HiG complicated or not with AA amyloidosis (AAA) (n=33): We finally found out 3 gene candidates in 3 different patients including on NLRP2 inflammasome. One manuscript is submitted on this result. We also studied CHIS in 25 elderly patients with FMF and already detected 15 somatic mutations in genes involved in clonal hematopoiesis, which has never been described before; one manuscript is in preparation on this topic.

Work package 3:

GCA patients (N=43): CH in PBMC have been found in 49% patients, including 60% epigenetics pathways and 30% spliceosome. CH was observed in 3 out of 4 patients in the temporal artery. Using spectral cytometry, increased CD62L expression on PMN was found in GCA patients with active disease compared with controls, MDS/CMML-CHIS and others vasculitis. In addition, GCA patients in remission showed significant decrease of CD62L expression.

Work package 4:

First, we have shown that Red cells in VEXAS are normal without morphological abnormalities, probably from residual hematopoiesis (normal, clonal or MDS). We are currently studying protein Ubiquitination that we expect to be normal in peripheral red cells to confirm this hypothesis. Second, we have studied erythropoiesis by performing CRISPR KI of UBA1 mutations and show that erythroid progenitors are dying as a consequence of p53 accumulation, which may explain why no abnormal red cells are observed. In contrast, Monocytes and neutrophils development is less affected with normal differentiation, no apoptosis but a slight proliferation diminution.

VERBATIM

“We obtained results for all 4 works packages, at cytokine, cellular and genomic levels. These findings provide a better understanding the involvement of clonal hematopoiesis in various disorders. In 2023, 2 oral communications have been accepted for a national congress and 3 publications are submitted or in writing (WP 2 and 3).”

RECENT PUBLICATIONS

Clinical features and genomic landscape of myeloproliferative neoplasm (MPN) patients with autoimmune and inflammatory diseases (AID). Elessa D, Zhao LP, de Oliveira RD, Maslah N, Soret-Dulphy J, Verger E, Marcault C, Parquet N, Fenaux P, Adès L, Raffoux E, Giraudier S, Fain O, Cassinat B, Kiladjian JJ, Mekinian A, Benajiba L. Leukemia. 2023 Aug;37(8):1741-1744. doi: 10.1038/s41375-023-01967-0. Epub 2023 Jul 11.PMID: 37433887
[Dysimmune manifestations associated with myelodysplastic neoplasms and chronic myelomonocytic leukaemias]. Jachiet V, Hadjadj J, Zhao LP, Chasset F, Fain O, Fenaux P, Mekinian A. Bull Cancer. 2023 Nov;110(11):1147-1155. doi: 10.1016/j.bulcan.2023.02.023. Epub 2023 Jul 4. PMID: 37414632 Review. French.
What role for somatic mutations in systemic inflammatory and autoimmune diseases associated with myelodysplastic neoplasms and chronic myelomonocytic leukemias? Zhao LP, Sébert M, Mékinian A, Fain O, Espéli M, Balabanian K, Dulphy N, Adès L, Fenaux P. Leukemia. 2023 Jun;37(6):1186-1190. doi: 10.1038/s41375-023-01890-4. Epub 2023 Apr 6. PMID: 37024519 Review. No abstract available.
Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation. Boy M, Bisio V, Zhao LP, Guidez F, Schell B, Lereclus E, Henry G, Villemonteix J, Rodrigues-Lima F, Gagne K, Retiere C, Larcher L, Kim R, Clappier E, Sebert M, Mekinian A, Fain O, Caignard A, Espeli M, Balabanian K, Toubert A, Fenaux P, Ades L, Dulphy N. Nat Commun. 2023 Feb 3;14(1):588. doi: 10.1038/s41467-023-36193-w. PMID: 36737440 Free PMC article.
Clinical and pathological features of cutaneous manifestations in VEXAS syndrome: A multicenter retrospective study of 59 cases. Zakine È, Papageorgiou L, Bourguiba R, Mekinian A, Terrier B, Kosmider O, Hirsch P, Jachiet M, Audia S, Ardois S, Adélaïde L, Bigot A, Duriez P, Emile JF, Lazaro E, Fayard D, Galland J, Hié M, Humbert S, Jean A, Kostine M, Lacombe V, Le Guenno G, Lobbes H, Magy-Bertrand N, Marianetti-Guingel P, Mathian A, Outh R, Saillard C, Samson M, Vial G, Bouaziz JD, Moguelet P, Chasset F; National French VEXAS Study Group (NFVS). J Am Acad Dermatol. 2023 Apr;88(4):917-920. doi: 10.1016/j.jaad.2022.10.052. Epub 2022 Nov 5. PMID: 36343774
A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML. Mekinian A, Zhao LP, Chevret S, Desseaux K, Pascal L, Comont T, Maria A, Peterlin P, Terriou L, D’Aveni Piney M, Gourin MP, Vey N, Rauzy OB, Grobost V, Bezanahary H, Dimicoli-Salazar S, Banos A, Wickenhauser S, De Renzis B, Durot E, Natarajan-Amé S, Voillat L, Chermat F, Lemaire K, Jachiet V, Himberlin C, Thépot S, Diaz JMT, Frenzel L, Gyan E, Denis G, Hirsch P, Kosmider O, Ades L, Fain O, Fenaux P. Leukemia. 2022 Nov;36(11):2739-2742. doi: 10.1038/s41375-022-01698-8. Epub 2022 Sep 14. PMID: 36104395