Abstract
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.
Highlights
Myelodysplastic syndrome (MDS) is a heterogenic group of diseases characterized by accumulation of somatic mutations [1,2,3], alterations in the bone marrow niches [4], various pathological events in the immune system, including pyroptosis and autoimmune bone marrow damage [5, 6], tumor escape at later stages [7] and ineffective hematopoiesis as a result of aforementioned events
The analysis of the checkpoint proteins expression in the bone marrow of MDS and acute myeloid leukemia (AML) patients demonstrated that myeloid cells express different checkpoint ligands and receptors, including CD80, CD86 and PD-1L [14,15,16]
A significant number of mutations was observed in the checkpoint genes: 46% of patients had mutations in LAG3, 20% in CTLA4, 23% in B7-H3, 14% in PD-1 and 3% in PD-1L
Summary
Myelodysplastic syndrome (MDS) is a heterogenic group of diseases characterized by accumulation of somatic mutations [1,2,3], alterations in the bone marrow niches [4], various pathological events in the immune system, including pyroptosis and autoimmune bone marrow damage [5, 6], tumor escape at later stages [7] and ineffective hematopoiesis as a result of aforementioned events. The current standard of care in high-risk MDS are hypomethylating agents [9, 10], which significantly improve time to progression and survival, but only in the minority of patients they induce complete remission (CR). Checkpoint and micro-RNA-associated mutations in MDS transplantation (SCT), but even in candidates in the modern era of advanced supportive care the results are generally worse than in CR of acute leukemia with only 30–40% of overall survival in 5 years [11, 12]. The best response observed in the clinical studies of checkpoint inhibitors was “stable disease”, despite the fact that some patients had stabilization for a long period of time, indicating the potential efficacy of these agents in MDS [17]. The other checkpoint inhibitors, like anti-TIM3 and anti-CD47, have a more promising response rate, but longer follow up is required to determine whether this response translates into long-term remission [18, 19]
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