High mutation burden in the checkpoint and micro-RNA processing genes in myelodysplastic syndrome.

A number of sequencing studies identified the prognostic impact of somatic mutations in myelodysplastic syndrome (MDS). However the majority of them focused on methylation regulation, apoptosis and proliferation genes. Despite the number of experimental studies published on the role of micro-RNA processing and checkpoint genes in the development of MDS, the clinical data about mutational landscape in these genes is limited. We performed a pilot study which evaluated mutational burden in these genes and their association with common MDS mutations. High prevalence of mutations was observed in the genes studied: 54% had mutations in DICER1, 46% had mutations in LAG3, 20% in CTLA4, 23% in B7-H3, 17% in DROSHA, 14% in PD-1 and 3% in PD-1L. Cluster analysis that included these mutations along with mutations in ASXL1, DNMT3A, EZH2, IDH1, RUNX1, SF3B1, SRSF2, TET2 and TP53 effectively predicted overall survival in the study group (HR 4.2, 95%CI 1.3-13.6, p = 0.016). The study results create the rational for incorporating micro-RNA processing and checkpoint genes in the sequencing panels for MDS and evaluate their role in the multicenter studies.

Immune checkpoints bone marrow expression as the predictor of clinical outcome in myelodysplastic syndrome.

AIMS: In our single-center retrospective study we evaluated whether level of different checkpoint molecules in bone marrow biopsies at diagnosis affect the clinical course of patients with myelodysplastic syndrome (MDS). METHODS AND RESULTS: A consecutive cohort of 55 MDS patients treated in our center from 2003 to 2018 with available bone marrow biopsies at time of diagnosis was studied. We used a technique able to detect the expression of the following antigens: PD-1, PD-L1, PD-L2, LAG-3, Gal-9, TIM-3, CD80. The association between expression level and 3-year overall and relapse-free survival and time-to-progression was analyzed. Intensive expression of TIM-3 was observed in 100% of cases. Also, in most cases, moderate Gal-9 expression was observed. With 3-year follow-up disease progression was seen in 72.9% of patients with high CD80 level and 52.1% of patients with low CD80 level (p=0.04). PD-1, CTLA4 and TIM-3 ligands were co-expressed in the majority of patients. General checkpoint ligand expression level also was associated with increased 3-year incidence of progression: 67.2% of patients with high level of checkpoint ligands progressed, while in the group with low checkpoint ligand expression level progression was observed only in 33.3% of cases (p=0.059). There was an association between the expression of checkpoint molecules CD80, PD-L2, TIM3, the number of bone marrow blasts and risk according to IPSS and IPSS-R scales. CONCLUSIONS: Our preliminary study underlined heterogeneous immune checkpoint molecules expression in MDS and warrants further studies to define the role of this heterogeneity and develop optimal treatment approaches.