Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

Abstract

To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or À7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with À7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention.

Recurrent genetic defects on chromosome 7q in myeloid neoplasms

“…Targeted sequencing was performed by TruSeq custom amplicon (Illumina). Previously published microarray expression data were obtained on a cohort of 183 MDS patients (-5/del(5q), N = 41) and healthy controls (N = 17) (Supplementary Figure S1) [5,17]. www.impactjournals.com/oncotarget…”

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

“…To confirm that somatic gene mutations prime HSPCs for pyroptosis in MDSs, we performed comparative analyses of published gene expression profiles from human and murine SRSF2 (GSE65349) and U2AF1 mutants (GSE30195 and GSE66793) vs WT, TET2 knockout (GSE27816), and primary MDS (GSE19429) vs normal HSPCs and found uniform upregulation of pyroptosis effectors, consistent with transcriptional priming. [39][40][41][42][43] Importantly, in MDS BM specimens, BM plasma concentration of S100A9 positively correlated with NLRP3 MFI, percentage and MFI of plasma ASC specks, and the presence of SGMs and variant allele frequency (supplemental Figure 8). Furthermore, both the percentage and MFI of plasma ASC specks were significantly increased in MDS patients harboring SGMs (supplemental Figure 8D-E).…”

Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome

“…Reduced expression of BCL2 protein in NHD13 LK cells was confirmed by flow cytometry ( Figure 3B). Expression analysis of BCL2-related genes using a published array dataset of CD34 ϩ purified MDS BM cells 18 revealed a significant reduction in BCL2 in the del(5q) subset (supplemental Figure 3), where apoptosis was linked to activation of the intrinsic pathway. 4 Increased expression of the proapoptotic genes BID and PUMA and the antiapoptotic gene BCL-X were also observed in the del5q subset but these changes were less marked and were not reflected in the NHD13 progenitors.…”