Biology subjects

Ciesla, M.

Publications and source records attributed to Ciesla, M..

5 recordsLinked to original sources

bioRxiv2024

NK cells control the progression of myelodysplastic syndrome but become initial disease target in NUP98-HOXD13 mouse model

Studies in NUP98/HOXD13 mouse model (NHD13tg), progressing from myelodysplastic syndrome (MDS) to different forms of leukemia, demonstrated that T cells had a limited anti-leukemia effect, suggesting the involvement of other immune cells. Natural killer (NK) cells control viral infection and cancer. In MDS and acute myeloid leukemia (AML), patients often acquire disease-induced NK cell dysfunctions. Here, we report that NK cells from NHD13tg mice were reduced before the MDS-onset and specific NK cell depletion accelerated the disease progression and severity. NK cells from NHD13tg mice showed perturbed differentiation and impaired IL-15/IL-2 responses. These defects were cell-intrinsic and mainly affected the KLRG1+ mature NK cells. The expression of Nfil3, Klf2 and Id2 genes, crucial for NK cell development, homeostasis and IL-15 responsiveness, was altered in immature NK cells from NHD13tg mice. Interestingly, these genes were changed in MDS and AML bone marrow patient-samples compared to healthy donors. Our findings highlight a critical role for NK cells in controlling MDS progression and identify new genetic markers for MDS and AML.

immunology↗

bioRxiv2023

PP2A inhibition instructs spliceosome phosphorylation to create splicing vulnerability in colon adenocarcinoma

Protein phosphatase 2A (PP2A) is a versatile enzyme affecting many aspects of cellular physiology. However, it remains unclear which of the cellular processes are most perturbed upon PP2A inhibition and how these perturbations could be exploited therapeutically. We report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to PP2A inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Altered phosphorylation endows LB-100-treated colorectal adenocarcinoma cells with differential splicing patterns. In PP2A-inhibited cells, over 1000 events of exon skipping and intron retention affect regulators of genomic integrity. Finally, LB-100-evoked alternative splicing is predicted to be a source of neoantigens that can improve cancer treatment responses to immune modulators. Our findings provide a potential explanation for the pre-clinical and clinical observations that PP2A inhibition sensitizes cancer cells to immune checkpoint blockade and genotoxic agents.

cancer biology↗

bioRxiv2022

Enhanced protein synthesis is a defining requirement for neonatal B cell development

The LIN28B RNA binding protein exhibits a ontogenically restricted expression pattern and is a key molecular regulator of fetal and neonatal B lymphopoiesis. It enhances the positive selection of CD5+ immature B cells early in life through amplifying the CD19/PI3K/c-MYC pathway and is sufficient to reinitiate self-reactive B-1a cell output when ectopically expressed in the adult. In this study, interactome analysis in primary B cell precursors showed direct binding by LIN28B to numerous ribosomal protein transcripts, consistent with a regulatory role in cellular protein synthesis. Induction of LIN28B expression in the adult setting is sufficient to promote enhanced protein synthesis during the small Pre-B and immature B cell stages, but not during the Pro-B cell stage. This stage dependent effect was dictated by IL-7 mediated signaling, which masked the impact of LIN28B through an overpowering stimulation on the c-MYC / protein synthesis axis in Pro-B cells. Importantly, elevated protein synthesis was a distinguishing feature between neonatal and adult B cell development that was critically supported by endogenous Lin28b expression early in life. Finally, we used a ribosomal hypomorphic mouse model to demonstrate that subdued protein synthesis is specifically detrimental for neonatal B lymphopoiesis and the output of B-1a cells, without affecting B cell development in the adult. Taken together, we identify elevated protein synthesis as a defining requirement for early-life B cell development that critically depends on Lin28b. Our findings offer new mechanistic insights into the layered formation of the complex adult B cell repertoire.

immunology↗

bioRxiv2021

A Non-Canonical Function of Arabidopsis ERECTA Proteins in Gibberellin Signaling

The Arabidopsis ERECTA family (ERf) of leucine-rich repeat receptor-like kinases (LRR-RLKs), comprising ERECTA (ER), ERECTA-LIKE 1 (ERL1) and ERECTA-LIKE 2 (ERL2), control epidermal patterning, inflorescence architecture, stomata development, and hormonal signaling. Here we show that the er/erl1/erl2 triple mutant exhibits impaired gibberellin (GA) biosynthesis and perception alongside broad transcriptional changes. ERf proteins interact in the nucleus, via kinase domains, with the SWI3B subunit of the SWI/SNF chromatin remodeling complex (CRCs). The er/erl1/erl2 triple mutant exhibits reduced SWI3B protein level and affected nucleosomal chromatin structure. The ER kinase phosphorylates SWI3B in vitro, and the inactivation of all ERf proteins leads to the decreased phosphorylation of SWI3B protein in vivo. Correlation between DELLA overaccumulation and SWI3B proteasomal degradation together with the physical interaction of SWI3B with DELLA proteins explain the lack of RGA accumulation in the GA- and SWI3B-deficient erf mutant plants. Co-localization of ER and SWI3B on GID1 (GIBBERELLIN INSENSITIVE DWARF 1) DELLA target gene promoter regions and abolished SWI3B binding to GID1 promoters in er/erl1/erl2 plants supports the conclusion that ERf-SWI/SNF CRC interaction is important for transcriptional control of GA receptors. Thus, the involvement of ERf proteins in transcriptional control of gene expression, and observed similar features for human HER2 (Epidermal Growth Family Receptor-member), indicate an exciting target for further studies of evolutionarily conserved non-canonical functions of eukaryotic membrane receptors. ONE SENTENCE SUMMARYERECTA leucine-rich receptor-like kinase and SWI3B subunit of SWI/SNF chromatin remodeling complex cooperate in direct transcriptional control of GID1 genes in Arabidopsis.

plant biology↗

bioRxiv2018

Heme oxygenase-1 deficiency affects bone marrow niche and triggers premature exhaustion of hematopoietic stem cells.

While intrinsic changes in aging hematopoietic stem cells (HSCs) are well-characterized, it remains unclear how hematopoietic niche affects HSC aging. Here, we demonstrate that cells in the niche -- endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs) -- highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. RNA-sequencing shows that ECs and CARs from HO-1-deficient animals (HO-1-/-) produce less hematopoietic factors. Consequently, HSCs from young HO-1-/- animals lose quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature aging on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature aging and may restore the function of aged HSCs.

cell biology↗