Biology subjects

Rouault-Pierre, K.

Publications and source records attributed to Rouault-Pierre, K..

4 recordsLinked to original sources

bioRxiv2022

HNRNPA2B1 controls an unfolded protein response-related prognostic gene signature in prostate cancer

HNRNPA2B1 is associated with prostate cancer (PC) disease aggressiveness and underlies pro-tumourigenic cellular stress responses. By analysing >500 PC transcriptomes, we reveal that HNRNPA2B1 over-expression is associated with poor patient prognosis and stress response pathways. These include the "protein processing in the endoplasmic reticulum" (ER) pathway, which incorporates the unfolded protein response (UPR). By RNA-sequencing of HNRNPA2B1-depleted cells PC cells, we identified HNRNPA2B1-mediated down-regulation of UPR genes including the master ER-stress sensor IRE1, which induces ER proteostasis. Consistent with IRE1 down-regulation in HNRNPA2B1-depleted cells, we observed reduced splicing of the IRE1-target and key UPR effector XBP1s. Furthermore, HNRNPA2B1 depletion up-regulates expression of the IRE1-dependent decay (RIDD) target gene BLOC1S1, which is degraded by activated IRE1. We identify a HNRNPA2B1-IRE1-XBP1-controlled four gene prognostic biomarker signature (HIX) which classifies a subgroup of primary PC patients at high risk of disease relapse. Pharmacological targeting of IRE1 attenuated HNRNAPA2-driven PC cell growth. Taken together, our data reveal a putative novel mechanism of UPR activation in PC by HNRNPA2B1, which may promote an IRE1-dependent yet potentially-targetable recurrent disease phenotype.

cancer biology↗

bioRxiv2022

A dual role for the RNA helicase DHX34 in NMDand pre-mRNA splicing and its function inhematopoietic differentiation

The DExD/H-box RNA helicase DHX34 is a Nonsense-mediated decay (NMD) factor that together with core NMD factors co-regulates NMD targets in nematodes and in vertebrates. Here, we show that DHX34 is also associated with the human spliceosomal catalytic C complex. Mapping of DHX34 endogenous binding sites using Cross-Linking Immunoprecipitation (CLIP) revealed that DHX34 is preferentially associated with pre-mRNAs and locates at exon-intron boundaries. Accordingly, we observed that DHX34 regulates a large number of alternative splicing (AS) events in mammalian cells in culture, establishing a dual role for DHX34 in both NMD and pre-mRNA splicing. We previously showed that germline DHX34 mutations associated to familial Myelodysplasia (MDS)/Acute Myeloid Leukemia (AML) predisposition abrogate its activity in NMD. Interestingly, we observe now that DHX34 regulates the splicing of pre-mRNAs that have been linked to AML/MDS predisposition. This is consistent with silencing experiments in hematopoietic stem/progenitor cells (HSPCs) showing that loss of DHX34 results in differentiation blockade of both erythroid and myeloid lineages, which is a hallmark of AML development. Altogether, these data unveil new cellular functions of DHX34 and suggests that alterations in the levels and/or activity of DHX34 could contribute to human disease.

molecular biology↗

bioRxiv2022

Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death.

Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a novel connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.

cancer biology↗

bioRxiv2021

Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Transformation

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in elderly individuals. In this work, we analyzed the transcriptome of human HSCs purified from young and elderly healthy donors, as well as MDS patients, identifying transcriptional alterations following eight different patterns of expression. While aging-associated lesions seemed to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detected the upregulation of the transcription factor DDIT3. Overexpression of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis. Such effect was associated with downregulation of transcription factors required for normal erythropoiesis, and with a failure in the activation of their transcriptional programs. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia was able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing MDS patients. STATEMENT OF SIGNIFICANCEThis study defines how human aging and MDS development are characterized by transcriptional alterations in HSCs that follow different patterns, some of which may contribute to myeloid transformation. Among them, we demonstrate how MDS-specific upregulation of DDIT3 in HSCs induces dyserythropoiesis, while its knockdown in HSPCs from MDS patients restores proper erythroid differentiation.

cancer biology↗