Hematopoietic stem cells of lower-risk MDS patients with rapid progression show quiescent-like cell state similar to that of higher-risk MDS cells

Abstrakt

Background and aims

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal diseases affecting maturation and differentiation of hematopoietic stem cells (HSCs). The disease is associated with genomic instability, we thus focused on expression of DNA repair genes to investigate the possible role of DNA repair impairment in the MDS pathogenesis.

Methods

We sequenced RNA from bone marrow (BM) CD34+ cells from diagnostic samples of 109 MDS patients. FFPE BM sections were immunohistochemically stained to detect RAD51 protein.

Results

Genes of mismatch repair, nucleotide excision repair, homologous recombination, and Fanconi anemia repair pathways were downregulated in higher-risk MDS (HR-MDS) compared to lower-risk MDS (LR-MDS). The impairment of DNA repair pathways in HR-MDS was observed at the protein level by detecting RAD51 on FFPE BM sections. The mentioned DNA repair pathways are primarily employed by proliferating HSCs for repair, suggesting that most of HR-MDS HSCs show quiescent-like cell state. LR-MDS samples which clustered with HR-MDS showed a high predominance of patients who rapidly progressed within 20 months and/or carried mutations in genes associated with adverse prognosis, such as RUNX1, U2AF1, ASXL1, and TP53. Conversely, several HR-MDS samples clustered within LR-MDS. We suggest that in those samples, a subset of HSCs that had acquired a proliferative potential prevailed during escaping anticancer barrier as observed in AML cells (Esposito & So, 2014).

Conclusions

Herein, we showed that HR-MDS and progressive LR-MDS HSCs predominate in quiescent-like cell state and that DNA repair expression profiles may be predictive of adverse outcome.