Biology subjects

Laplane, L.

Publications and source records attributed to Laplane, L..

3 recordsLinked to original sources

bioRxiv2024

CXCL8 secreted by immature granulocytes inhibits wildtype hematopoiesis in chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrated early clonal dominance with few residual wildtype hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explores the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs can be detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation is a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behave as myeloid-derived suppressor cells. Bulk and single cell RNA sequencing revealed a pro-inflammatory status of iGRAN that secrete multiple cytokines of which CXCL8 at the highest level. This cytokine inhibits the proliferation of wildtype but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors are epigenetically downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restore wildtype HSPC proliferation, suggesting that relieving CXCL8 selective pressure on wildtype HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis.

cancer biology↗

bioRxiv2024

Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

cancer biology↗

bioRxiv2023

Transcriptomic landscape of posterior regeneration in the annelid Platynereis dumerilii

Background: Restorative regeneration, the capacity to reform a lost body part following amputation or injury, is an important and still poorly understood process in animals. Annelids, or segmented worms, show amazing regenerative capabilities, and as such are a crucial group to investigate. Elucidating the molecular mechanisms that underpin regeneration in this major group remains a key goal. Among annelids, the nereididae Platynereis dumerilii (re)emerged recently as a front-line regeneration model. Following amputation of its posterior part, Platynereis worms can regenerate both differentiated tissues of their terminal part as well as a growth zone that contains putative stem cells. While this regeneration process follows specific and reproducible stages that have been well characterized, the transcriptomic landscape of these stages remains to be uncovered. Results: We generated a high quality de novo Reference transcriptome for the annelid Platynereis dumerilii. To do so, we produced and analyzed three RNA-sequencing datasets, encompassing five stages of posterior regeneration, along with blastema stages and non-amputated tissues as controls. We included these regeneration RNA-seq datasets, as well as embryonic and tissue-specific datasets from the literature to produce a Reference transcriptome. We used this Reference transcriptome to perform in depth analyzes of RNA-seq data during the course of regeneration to reveal the important dynamics of the gene expression, process with thousands of genes differentially expressed between stages, as well as unique and specific genes expression at each regeneration stage. The study of these genes highlighted the importance of the nervous system at both early and late stages of regeneration, as well as the enrichment of RNA-binding proteins (RBPs) during almost the entire regeneration process. Conclusions: In this study, we provided a high-quality de novo Reference transcriptome for the annelid Platynereis that is useful for investigating various developmental processes, including regeneration. Our extensive stage-specific transcriptional analysis during the course of posterior regeneration shed light upon major molecular mechanisms and pathways, and will foster many specific studies in the future.

genomics↗