Biology subjects

Cathelin, S.

Publications and source records attributed to Cathelin, S..

3 recordsLinked to original sources

bioRxiv2026

CD59 organizes the plasma membrane to sustain oncogenic Ras-MAPK signaling and is a targetable vulnerability in acute myeloid leukemia

Acute myeloid leukemia (AML) is a clinically heterogeneous disease. Although the genetic abnormalities associated with poor prognosis are well defined, how they drive unfavorable outcomes remains unclear. Using published gene-expression and dependency datasets, we searched for cell-surface protein-coding genes associated with poor survival and required for AML growth, prioritizing this class of proteins for its accessibility to biologics. This search identified CD59, a GPI-anchored protein with a canonical role in complement regulation, whose high mRNA expression correlates with adverse-risk genetics and stemness signatures. CD59 silencing impaired proliferation across genetically diverse AML cell lines, reduced leukemic burden, and extended survival in cell xenograft models. Moreover, CD59 expression was enriched on leukemic stem cells (LSCs), and its depletion impaired LSC self-renewal and primary AML engraftment in vivo while sparing normal hematopoiesis. Mechanistically, these effects reflected a non-canonical role for CD59 in sustaining Ras-MAPK signaling, whereby its loss depleted inner-leaflet phosphatidylserine and impaired Ras and c-Raf membrane recruitment and activation. rILYd4, a recombinant fragment of the bacterial toxin intermedilysin that binds and degrades CD59, recapitulated these effects and sensitized cells to venetoclax in vivo. These findings reveal CD59 as a critical regulator of Ras-MAPK signaling required for AML growth and nominate its rILYd4-mediated degradation as a therapeutic strategy.

cancer biology↗

bioRxiv2025

Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS

Myelodysplastic neoplasms (MDS) feature hematopoietic deficits driven in part by transcript splicing abnormalities. Thus far, such disease-driving transcripts have been identified in association with specific splicing factor mutations. However, it remains unclear whether there also exists a set of disease-wide conserved pathological transcripts, which drive MDS independently of mutational status. Here, we characterize an MDS-associated long isoform of MBD1 (MBD1-L) as the first described member of this class of transcripts. Overexpression of MBD1-L in healthy human HSPCs recapitulates archetypal defects of MDS including deficits in erythroid differentiation and reconstitution capacity. These defects arise from an isoform-specific switching of MBD1s binding behavior, refocusing its heterochromatin-promoting activity from methylated to unmethylated CpGs and enacting broad downregulation of CpG-rich promoters as well as secondary epigenetic effects mediated by its downstream target BCOR. Remarkably, we also find that directly reversing abnormal MBD1 splicing in primary human MDS using nanoparticle-encapsulated ASOs enhances erythroid differentiation. Key pointsO_LIGlobal mis-splicing of MBD1 represents a novel gain-of-function epigenetic axis driving erythropoietic and proliferative defects in MDS. C_LIO_LIASO based depletion of pathogenic MBD1 transcripts restores erythroid differentiation, advancing RNA-based therapies for MDS. C_LI

cancer biology↗

bioRxiv2025

Stress Granules Underlie Acute Myeloid Leukemia Stem Cell Survival and Stress Adaptation

The link between cancer maintenance and an ability to sustain continued growth through stresses conferred by the cancer state itself is growing. However, there are significant gaps in our understanding of how this stress is managed, particularly at the level of cancer initiating cells. Here, we identify proteins comprising the dynamic, stress-adaptive ribonucleoprotein complexes known as stress granules (SG) to be enriched among the factors essential for leukemic stem cell (LSC)-driven leukemic propagation. Focusing on core SG nucleator G3BP1, we dissect the role of SGs in human acute myeloid leukemia (AML), their targetability, and the mechanisms they govern to uncover a novel propensity for AML, and in particular LSC-enriched fractions, to prime the expression of SG components, form SGs with greater fidelity and to be reliant on their establishment and continued integrity for LSC maintenance. We further unveil the transcript and protein interactome of G3BP1 in the AML context and show that consolidated control of innate immune signaling, and apoptosis repression is executed through regional binding specificity of G3BP1 to highly structured 3UTRs and cooperation with the RNA helicase UPF1 to mediate transcript decay in SGs. Altogether our findings advance novel fundamental principles of stress adaptation exploited in AML and LSCs that may extend to other cancers and uncover SGs as a novel axis for therapy development.

cancer biology↗