Here, we investigated the cytotoxic efficacy of talazoparib and APE1 inhibitor III, inhibitors of PARP1/2 and APE1, in primary CD34+ MDS/CMML cell samples (<i>n</i> = 8; 4 MDS and 4 CMML) and in primary CD34+ or CD34- AML cell samples (<i>n</i> = 18) in comparison to healthy CD34+ donor cell samples (<i>n</i> = 8).
Total RNA was extracted from CD34(+) bone marrow hematopoietic cells from healthy individuals (n = 10) and patients with MDS (n = 24) or chronic myelomonocytic leukemia (n = 19).
RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation.
In this study we show that ROS1 is abnormally activated in the CD34+ compartment of approximately 70% of CMML patients resulting in the activation of the Erk/Akt pathways through the Grb2/SOS complex thus revealing a central oncogenic role for ROS1 in CMML which might represent a molecular target.
We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples.