HIGH SERUM LONG-CHAIN OMEGA-3 FATTY ACIDS ARE ASSOCIATED WITH 6-MONTHLOWER DISEASE ACTIVITY IN EARLY RA: RESULTS FROM THE ESPOIR COHORT

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Serum Fatty Acid Profiles Are Associated with Disease Activity in Early Rheumatoid Arthritis: Results from the ESPOIR Cohort

Background: Long-chain omega-3 and omega-6 fatty acids (n-3, n-6 FAs) may modulate inflammation and affect the risk of developing rheumatoid arthritis (RA). However, whether n-3/n-6 FA status affects RA after disease onset is unknown. This study aimed to assess whether FA profiles are independently associated with disease activity in a large prospective cohort of patients with early RA. Methods: Baseline serum FAs were quantified in 669 patients in the ESPOIR cohort. Principal component analysis identified three serum FA patterns that were rich in n-7–9, n-3 and n-6 FAs (patterns ω7–9, ω3 and ω6), respectively. The association of pattern tertiles with baseline variables and 6-month disease activity was tested using multivariable logistic regression. Results: Pattern ω3 was associated with low baseline and pattern ω6 with high baseline C-reactive protein level and disease activity. Both patterns ω3 and ω6 were associated with reduced odds of active disease after 6 months of follow-up (pattern ω3: odds ratio, tertile three vs. one, 0.49 [95% CI 0.25 to 0.97] and pattern ω6: 0.51 [0.28 to 0.95]; p = 0.04 and 0.03, respectively). Conclusions: In a cohort of early RA patients, a serum lipid profile rich in n-3 FAs was independently associated with persistently reduced disease activity between baseline and 6-month follow-up. An n-6 FA profile was also associated with lower 6-month disease activity

The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL) - the translocation defining a new T-ALL subtype in very young children.

The c-Myb transcription factor is essential for primitive and adult hematopoiesis, including in the T-cell lineage. The c-myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified two types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n=6 cases). Second, a genome wide copy-number analysis by array-CGH identified short somatic duplications which include C-MYB (MYB(dup), n=13 cases out of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared to other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to downregulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median 2.2 years-old) and with a proliferation/mitosis expression signature. By contrast, the MYB(dup) alteration was associated to the previously defined T-ALL subtypes

Clonal Hematopoiesis Driven By MDM4 Amplification Defines a Canonical Route Towards Secondary MDS/AML in Fanconi Anemia Patients

International audienceAbstract Introduction Fanconi anemia (FA) is the most frequent inherited DNA-repair disease in human, driving hematopoietic stem cell (HSC) failure in children and a major predisposition to poor-prognosis myelodysplastic syndrome (MDS) and acute leukemia (AML) in children or young adults. MDS/AML secondary to FA have a dismal prognosis in this frail population with a high chemotherapy-related toxicity. How bone marrow (BM) cells progress to myeloid malignancies in a background of cell intrinsic genomic instability and stem cell exhaustion is still poorly understood. Here we aimed to identify the molecular and functional determinants of BM progression to MDS/AML in FA patients. Methods We studied a cohort of 335 FA patients, representing virtually all FA patients seen in France from 2002 to 2020. We performed longitudinal clinical studies (cytopenia, BM morphology and staging, HSCT, survival), somatic genomics (karyotype, myeloid cancer gene panel, aCGH, WES, WGS), expression analysis by RNAseq on clonal cells, and functional studies (gene modulation in HSPCs, transgenic MDM4 mice, CFU and competitive engraftment experiments). Paired clonal BM and skin fibroblasts samples were available for 62 MDS/AML FA patients; WES and WGS files from age-matched non FA MDS/AML were used as controls. Results 98 out of 335 patients (29%) experienced clonal evolution, first seen at a median age of 13y, including 51 (15%) with blastic evolution (>5% BM blasts, median age 16y). Unbalanced chromosomal translocations rather than point mutations underlaid clonal evolution in comparison to age-matched, sporadic (non-FA) AML cases. The most prominent driver lesion was chromosome 1q duplication (1q+), found in 52% of the clonal FA patients, while other recurrent lesions were gain of 3q (3q+/EVI1; 40%), translocations/del/mut involving the RUNX1 gene (35%), monosomy 7/7q- (31%), and signaling gene mutations (18%). Based on longitudinal studies and ranking models, we evidenced that 1q+ occurred early, yielding preleukemic clonal hematopoiesis, whereas 3q+, -7/del7q, RUNX1 and signaling mutations occurred later along with BM transformation. Regarding genomic instability, WGS analysis of FA AML cells revealed a unique mutational signature that shares features with BRCA-related solid cancers [homologous recombination deficient (HRD)-type substitution signature, accumulation of small/intermediate-size deletions and large structural variants (SV)]. SV breakpoint analysis identified microhomology-mediated end joining (MM-EJ, also known as Alt-EJ) as the preferential DNA repair mechanism in the FA context. Specifically, a fragile site in the 1q pericentromeric repeated region underlaid 1q+ translocations. Next, we found that the MDM4 oncogene, a negative modulator of p53 response located in the minimal 1q duplicated region, was overexpressed in 1q+ but not in clonal non-1q FA cells. We hypothesized that 1q+ may attenuate the FA-associated p53 pathway hyperactivation through increased gene dosage of MDM4. Consistently, RNA-seq of patient cells before and after clonal progression showed p53 pathway activation before clonal evolution and subsequent p53 downregulation along with 1q+. When evaluated in vitro by CFU assay, lentiviral overexpression of MDM4 rescued clonogenicity defect of HSCPs from both FA patients and Fanc-/- mice, at the same level as TP53 knockdown. We produced a transgenic mouse bearing a duplicated Mdm4 locus and showed that MdM4 overexpression conferred an advantage to FA-like HSPCs in competitive transplant experiments, modeling clonal hematopoiesis. Exposure of 1q+ FA cells to Mdm4 inhibitors raised therapeutic potential. Conclusions The somatic genomic landscape of FA MDS/AML reveals a unique FA mutational signature, characterized by structural rearrangements and copy number abnormalities rather than point mutations. Our results define a canonical oncogenic route towards secondary MDS/AML in FA patients, in which the early modulation of the p53 pathway through 1q+/MDM4 oncogene overexpression plays a pivotal role, raising novel monitoring and therapeutic prospects for the FA patients. Disclosures Sebert: BMS: Consultancy; Abbvie: Consultancy. Dalle: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old