Session: 508. Bone Marrow Failure: Poster I
Hematology Disease Topics & Pathways:
Diseases, Bone Marrow Failure, Biological Processes, Cell Lineage, Study Population, immune mechanism
In this scenario, we hypothesize that defects in both class I and II HLA loci may constitute different patterns of immune escape, reducing respectively CD8+ and CD4+ related activation and thus contributing to rescue hematopoietic stem cells from the immune attack. Furthermore, our idea is that the immune-escape environment may be related to the grade of HLA evolutionary divergence (HED), a metric that, accounting for the degree of structural diversity within a particular locus, represents an indirect measure of the antigenic landscape that the hematopoietic target cell is able to present (see abstract #:142693).
Using a deep targeted HLA NGS panel and a newly developed in-house bioinformatic pipeline (characterized by stringent criteria for alignment, preprocessing and variant calling in the HLA region, based on the IPD IMGT/HLA database, Fig.A), we studied a large cohort of patients with idiopathic bone marrow failures (AA n=75, AA/MDS=10). In addition, we determined the impact of inter-loci HED on the probability to acquire somatic hits in HLA genes.
Overall, 29 somatic HLA mutations were found in 16 patients (18%) at a median VAF of 11% (range: 2-93%):12 in class I (41%) and 17 in class II (59%), with 5 patients carrying mutations in both classes (Fig.B, C, D). The majority of those events (N=21, 72%) occurred in subjects also harbouring a PNH clone of small size (12 out 16 patients, median PNH clone size 1% [range:1-46%]). Most mutated loci were A and C for class I and DQB1 for class II (Fig. C, D); 9 mutations were identified as missense, with disruptive changes, 7 were intronic indels while 13 hits were localized in 5’ or 3’ untranslated regions (UTRs) (Fig.E, F). Through a computational prediction of the HLA regulatory domains involved in the UTR aberrations, we identified domains essential for the binding of GATA-1, RXRbeta, SP-1 and NFKB. The impairment of those regions may affect the transcription of HLA complexes. AA HLA mutant cases had more frequently a severe disease at diagnosis (severe AA: 81% vs. 60%, respectively in HLA mutated vs non mutated cases) and were in most part responders to immunosuppressive therapy (complete/partial responses: 75% vs 50% in HLA mutated vs non mutated patients). Within the AA/MDS group instead HLA mutations were found in 4 out of 10 patients (40%), including of note three -7/del7q cases.
Using Pierini and Lenz algorithm3 to determine inter-class HED, we found that HLA mutations tended to occur more often in patients with a high inter-class mean HED (94% vs 72% in non mutated group, p=.001, Fig. G), consistent with the idea that higher structural diversity of HLA molecules may induce more pervasive auto-immune responses, stronger immune pressure and ultimately the establishment of immune-escape mechanisms.
In summary, our results indicate the importance of class-I and -II HLA loci somatic hits as markers of autoimmunity and thereby the severity of the immune selection pressure, configuring possibly alternative mechanisms of immune-escape, in addition to immune privileged PNH clones. This environment may ultimately facilitate leukemic clonal expansion in AA-MDS setting.
Disclosures: Patel: Alexion: Other: educational speaker, Speakers Bureau. Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding. Maciejewski: Novartis, Roche: Consultancy, Honoraria; Alexion, BMS: Speakers Bureau.