Cell Type-Specific Deregulation of Polypyrimidine Tract- Binding Proteins (PTBPs) Drive Aberrant Splicing in Multiple Myeloma (MM) and Acute Myeloid Leukemia (AML)

Genome-wide transcriptome profiling detected an increased splicing alterations in MM and AML. While these malignancies are derived from different cell linages, their tumor cells acquire similar aberrant splicing (AbSp), mostly intron retentions. To delineate AbSp mechanism in MM/AML, we focused on PTBPs (1/2/3) that play a critical role in intron excision. We have previously reported deregulated expression of splicing factors (SFs) in MM/AML patient and healthy donor (HD) bone marrow (BM). As MM progressed, PTBP1/2 progressively increased, and PTBP3 gradually decreased (ASH 2017). In AML, PTBP2/3 upregulation and PTBP1 downregulation were detected in patient samples in which increased intron retentions were identified by genome-wide splicing analysis (CCR 2015).Here, these findings were validated by TaqMan assays for PTBPs in 48 MM and 325 AML patient samples, 16 MM/AML cell lines, and in plasma cells (PCs) and CD34+cells from 14 HDBM. Results were consistent with differential expressions of PTBPs in MM/AML previously analyzed. Upregulation of PTBP1/2 and PTBP2/3 proteins were detected in MM and AML cell lines, respectively. PTBP1/2 upregulation was pronounced when MM cell lines were cocultured with BM stromal cells (MMBMSC) derived from MM patients' BM. Importantly, we detected increased proliferation and decreased apoptosis in MM/AML cell lines overexpressing PTBPs. These effects were most evident after coculturing MM cell lines with MMBMSC as compared to HDBMSC.To evaluate...
Source: Blood - Category: Hematology Authors: Tags: 602. Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation: Poster III Source Type: research