DHX15 affects AML1‐ETO9a splicing together with HNRNPL, RBM33 in AML1‐ETO‐positive acute myeloid leukaemia
TL;DR
Findings support an association between DHX15, HNRNPL, RBM33 and AE9a splicing and suggest their contribution to leukemogenic progression in AE+ AML and three‐dimensional structure prediction suggests a sophisticated regulatory complex formation.
Abstract
The AML1‐ETO (AE) fusion gene, resulting from t(8;21)(q22;q22), represents a prevalent subtype of acute myeloid leukaemia (AML). Retention of exon 9a between exon 8 and 9 of the ETO (RUNX1 Partner Transcriptional Co‐Repressor 1, also name RUNX1T1) gene generates the oncogenic AML1‐ETO9a (AE9a) splice variant. Here, we uncover the potential involvement of RNA (ribonucleic acid) helicase DHX15 (DEAH‐box helicase 15) in AE9a splicing and AML progression. Clinically, higher expressed DHX15 is associated with increased AE9a/AE abundance and poor outcomes in AE‐positive (AE+) AML patients. DHX15 knockdown impaired cell proliferation, induced S/G2 cell‐cycle arrest in vitro and prolonged overall survival in AE+ leukaemia‐bearing mice in vivo. In addition, DHX15 knockdown reduced AE and AE9a expression, and RNA immunoprecipitation revealed DHX15 bound to AE and AE9a transcripts and RNA pull‐down assay showed a selective interaction of HNRNPL and RBM33 with AE9a transcripts. Three‐dimensional structure prediction suggests a sophisticated regulatory complex formation involving DHX15, HNRNPL (heterogeneous nuclear ribonucleoprotein L) and RBM33 (RNA binding motif protein 33). Further, HNRNPL and RBM33 gene expression positively correlated with AE9a levels in AE+ AML samples. Downregulation of HNRNPL and RBM33 reduced AE9a expression in Kasumi‐1 cells. Collectively, our findings support an association between DHX15, HNRNPL, RBM33 and AE9a splicing and suggest their contribution to leukemogenic progression in AE+ AML.