Abstract
The Revised International Prognostic Score and some somatic mutations in myelodysplastic syndrome (MDS) are independently associated with transformation to acute myeloid leukemia (AML). Immunity has also been implicated in the pathogenesis of MDS, although the underlying mechanism remains unclear. We performed a SNP array on chromosome 6 in CD34+ purified blasts from 19 patients diagnosed with advanced MDS and 8 patients with other myeloid malignancies to evaluate the presence of loss of heterozygosity (LOH) in HLA and its impact on disease progression. Three patients had acquired copy-neutral LOH (CN-LOH) on 6p arms, which may disrupt antigen presentation and act as a mechanism for immune system evasion. Interestingly, these patients had previously been classified at low risk of AML progression, and the poor outcome cannot be explained by the acquisition of adverse mutations. LOH HLA was not detected in the remaining 24 patients, who all had adverse risk factors. In summary, the clinical outcome of patients with advanced MDS might be influenced by HLA allelic loss, wich allows subclonal expansions to evade cytotoxic-T and NK cell attack. CN-LOH HLA may therefore be a factor favoring MDS progression to AML independently of the somatic tumor mutation load.
Highlights
Myelodysplastic Syndromes (MDS) are a range of heterogeneous clonal hematologic diseases characterized by ineffective hematopoiesis and a tendency to develop acute myeloid leukemia (AML) [1]
Of the total of 27 patients included in the study, in 14 of the 21 patients with myelodysplastic syndrome (MDS), sAML, or chronic myelomonocytic leukemia (CMML), the baseline International Prognostic Scoring System (IPSS)-R score was Very High Risk (VHR, n= 6), High Risk (HR, n=1), Intermediate (n=3), or Low/Very Low Risk (LR or VLR, n=4); no data were available for 7 patients
-locus or -allele loss, among others, and these changes have been attributed to multiple molecular mechanisms [13, 39, 40]
Summary
Myelodysplastic Syndromes (MDS) are a range of heterogeneous clonal hematologic diseases characterized by ineffective hematopoiesis and a tendency to develop acute myeloid leukemia (AML) [1]. Given the heterogeneity of the disease, several prognostic scoring systems are currently used to stratify patients according to the risk of AML development, including the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R), which incorporates a cytogenetic risk classification [2, 3]. The most frequently mutated genes in MDS patients are involved in RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2) and www.oncotarget.com in epigenetic regulation of DNA, including methylation (TET2, DNMT3A, IDH1/2) and chromatin regulation (ASXL1, EZH2) processes. Markers of high molecular risk (TP53, EZH2, ETV6, RUNX1, ASXL1, SRSF2) have been defined that predict worse overall survival and a greater risk of leukemic transformation and post-transplantation relapse, independently of prognostic scores, whereas mutations in SF3B1 have been associated with improved survival outcomes [7,8,9]
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