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Targeting RNA-binding proteins in acute and chronic leukemia.

ABSTRACT: RNA-binding proteins (RBPs) play a crucial role in cellular physiology by regulating RNA processing, translation, and turnover. In neoplasms, RBP support of cancer-relevant expression of alternatively spliced, modified, and stabilized mRNA transcripts is essential to self-renewal, proliferation, and adaptation to stress. In this review, we assess the impact of key families of RBPs in leukemogenesis, review progress in targeting those proteins with small molecules, and discuss how multilevel composition of posttranscriptional regulation of gene expression could be used for potential therapies in acute and chronic leukemia.

SUBMITTER: Elcheva IA

PROVIDER: S-EPMC7868134 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Targeting RNA-binding proteins in acute and chronic leukemia.

Elcheva Irina A IA Spiegelman Vladimir S VS

Leukemia 20201104 2

RNA-binding proteins (RBPs) play a crucial role in cellular physiology by regulating RNA processing, translation, and turnover. In neoplasms, RBP support of cancer-relevant expression of alternatively spliced, modified, and stabilized mRNA transcripts is essential to self-renewal, proliferation, and adaptation to stress. In this review, we assess the impact of key families of RBPs in leukemogenesis, review progress in targeting those proteins with small molecules, and discuss how multilevel comp ...[more]

PMID: 33149266

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Project description:The members of the Poly(ADP-ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a "BRCAness phenotype." AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.

Dataset Information

Targeting RNA-binding proteins in acute and chronic leukemia.

Publications

Targeting RNA-binding proteins in acute and chronic leukemia.

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