Biology subjects

Stam, R. W.

Publications and source records attributed to Stam, R. W..

4 recordsLinked to original sources

bioRxiv2026

Menin maintains enhancer-promoter interactions in a leukemia-specific manner

Inhibition of the protein-protein interaction between Mixed Lineage Leukemia (MLL) and Menin is a promising therapy for both high-risk MLL-rearranged and NPM1-mutant (NPM1c) acute leukemias, yet the mechanistic basis of this dependency in distinct contexts remains unclear. By comparing the transcriptional responses of MLL::AF4 and NPM1c leukemia models to Menin inhibition, we find broad, acute transcriptional dysregulation in MLL::AF4 cells, but minor transcriptional consequences in NPM1c cells, despite similarities in Menin promoter occupancy. Using high-resolution Micro Capture-C, we discover that Menin drives enhancer activity and maintains enhancer-promoter contacts in MLL::AF4 cells but not in NPM1c cells. Crucially, Menin is also essential for patient-specific enhancer function in primary MLL-rearranged leukemia samples. Proteomic analysis further demonstrates that Menin associates with distinct transcriptional and elongation complexes in MLL::AF4 compared to NPM1c cells, supporting a context-dependent mechanism of action. Together, these findings establish that Menin is not a uniform transcriptional cofactor, but a context-dependent regulator of enhancer connectivity, and identifies enhancer-promoter architecture as a selective vulnerability in MLL-rearranged leukemia.

cancer biology↗

bioRxiv2024

Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression between patients

Genetic alterations alone cannot account for the diverse phenotypes of cancer cells. Even cancers with the same driver mutation show significant transcriptional heterogeneity and varied responses to therapy. However, the mechanisms underpinning this heterogeneity remain under-explored. Here, we find that novel enhancer usage is a common feature in acute lymphoblastic leukemia (ALL). In particular, KMT2A::AFF1 ALL, an aggressive leukemia with a poor prognosis and a low mutational burden, exhibits substantial transcriptional heterogeneity between individuals. Using single cell multiome analysis and extensive chromatin profiling, we reveal that much transcriptional heterogeneity in KMT2A::AFF1 ALL is driven by novel enhancer usage. Using high resolution Micro-Capture-C in primary patient samples, we also identify patient-specific enhancer activity at key oncogenes such as MEIS1 and RUNX2, driving high levels of expression of both oncogenes in a patient-specific manner. Overall, our data show that enhancer heterogeneity is highly prevalent in KMT2A::AFF1 ALL and may also be a mechanism that drives transcriptional heterogeneity in cancer more generally. Key PointsO_LILeukemia patients with the same driver mutations often display gene expression differences C_LIO_LIUsing chromatin profiling and high resolution 3C methods we show that enhancer heterogeneity drives gene expression differences C_LI

cancer biology↗

bioRxiv2022

A comprehensive single-cell expression atlas of human AML leukemia-initiating cells unravels the contribution of HIF pathway and its therapeutic potential

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML), and is driven by rare therapy-resistant leukemia-initiating stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling keeps cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to AML-LSC function and chemoresistance and is a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we provide a comprehensive single-cell expression atlas (119,000 cells) of AML cells and AML-LSCs in paired diagnostic-relapse samples from risk-stratified patients with AML. The HIF/hypoxia pathway is attenuated in AML-LSCs compared with differentiated AML cells, but is enhanced when compared with healthy hematopoietic cells. Accordingly, chemical inhibition cooperates with standard-of-care chemotherapy to impair leukemogenesis, substantially eliminating AML-LSCs. These findings support the HIF pathway as a stem cell regulator in human AML, and reveal avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.

cancer biology↗

bioRxiv2021

A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1

A significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 87 fusions with significant allele frequency across patients and shared functional impacts, suggesting common mechanisms across fusions. We further identified a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor SRRM1. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Supplementary analysis revealed that SRRM1 potentially modulates splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Our findings reveal a potential convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of the underlying gene fusion, and that could potentially complement current clinical strategies in infant B-ALL.

cancer biology↗