Biology subjects

Enlund, S.

Publications and source records attributed to Enlund, S..

3 recordsLinked to original sources

bioRxiv2025

METTL13 Promotes Pre-Leukemic Transformation and the Development of Pediatric Leukemia

Post-transcriptional RNA modifications, such as N6-methyladenosine (m6A) methylation and adenosine to inosine (A-to-I) editing, are critical regulators of hematopoietic stem cell (HSC) self-renewal and differentiation, yet their precise contributions to malignant transformation are not fully elucidated. In this study, we uncovered the epitranscriptomic landscape caused by knockdown of genes from the methyltransferase (METTL)-family in hematopoietic stem and progenitor cells (HSPCs). We identified both converging and distinct roles of METTL3 and METTL14, known members of the m6A writer complex, as well as orphan gene METTL13. Notably, METTL13 was uniquely upregulated by adenosine deaminase acting on RNA 1 (ADAR1) overexpression, while other METTL genes were downregulated. Knockdown of METTL13 altered the expression of multiple genes involved in oncogenic development in HSPCs. Furthermore, METTL13 was associated with a high-risk profile in pediatric T-cell acute lymphoblastic leukemia (T-ALL), and functional studies confirmed that METTL13 is required for T-ALL cell proliferation and survival both in vitro and in vivo. Collectively, our results indicate a previously unrecognized, oncogenic role for METTL13 in pre-leukemic transformation and T-ALL pathogenesis. SignificanceIn this study we uncovered a novel regulatory link between ADAR1 and the METTL-family of RNA methyltransferases in hematopoietic stem cells. Overexpression of ADAR1 uniquely upregulated METTL13 while suppressing other METTL genes. Loss of orphan gene METTL13 affected proliferation, apoptosis and p53 signaling in hematopoietic stem cells. Furthermore, loss of METTL13 suppressed cell proliferation and survival in pediatric T-cell acute lymphoblastic leukemia. Our findings suggest a potential role for METTL13 in pre-leukemia transformation and oncogenic development.

cancer biology↗

bioRxiv2024

A Distinct Alternative mRNA Splicing Profile Identifies the Oncogenic CD44 Transcript Variant 3 in KMT2A-Rearranged Pediatric T-cell Acute Lymphoblastic Leukemia Cells

T-cell acute lymphoblastic leukemia (T-ALL), which constitutes of 10-15% of all pediatric ALL cases, is known for its complex pathology due to pervasive genetic and chromosomal abnormalities. Although most children are successfully cured, chromosomal rearrangements involving the KMT2A (KMT2A) gene is considered a poor prognostic factor. In a cohort of 171 pediatric T-ALL samples we have studied differences in gene and splice variant patterns in KMT2A rearranged (KMT2A-r) T-ALL compared to KMT2A negative (KMT2A-wt) T-ALL samples. Our results have identified a distinct gene expression and splice variant expression pattern in pediatric KMT2A-r patient samples including significant expression of splicing regulatory markers ESRP1 and MBNL3. Additionally, the pro-survival long transcript variant of BCL2 were upregulated in KMT2A-r compared to KMT2A-wt T-ALL samples. Lastly, increased levels of activating methylation in the promoter region of CD44 were identified followed by an upregulation of the oncogenic transcript variant CD44v3 in KMT2A-r T-ALL. Together this suggests that CD44v3 could play a potential role as gene expression-based risk stratification of KMT2A-r rearranged T-ALL and could possibly serve as a therapeutic target using splicing modulators.

cancer biology↗

bioRxiv2023

The CNS Microenvironment Promotes Leukemia Cell Survival by Disrupting Tumor Suppression and Cell Cycle Regulation in Pediatric T-cell Acute Lymphoblastic Leukemia

A major obstacle in improving survival in pediatric T-cell acute lymphoblastic leukemia is understanding how to predict and treat leukemia relapse in the CNS. Leukemia cells are capable of infiltrating and residing within the CNS, where they interact with the microenvironment and remain sheltered from systemic treatment. These cells can survive in the CNS niche, by hijacking the microenvironment and disrupting normal functions, thus promoting malignant transformation. While the protective effects of the bone marrow niche have been widely studied, the mechanisms behind leukemia infiltration into the CNS and the role of the CNS niche in leukemia cell survival remain unknown. We have identified a dysregulated gene expression profile in CNS infiltrated T-ALL and CNS relapse, promoting cell survival, chemoresistance and disease progression. Furthermore, we discovered that interactions between leukemia cells and CNS microenvironment induce epigenetic alterations, such as changes in gene regulation and histone modifications, including H3K36me3 levels. These findings can be utilized to predict CNS infiltration and CNS relapse, therefore avoiding overtreatment and adverse effects caused by CNS directed therapy. Additionally, the identified genetic drivers of disease progression can serve as a first step towards identifying therapeutic targets, to sensitize the CNS niche to current therapeutic strategies.

cancer biology↗