ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.

Autor: Lin I; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Awamleh Z; Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada., Sinvhal M; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Wan A; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Bondhus L; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., Wei A; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada., Russell BE; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.; Department of Human Genetics, Division of Clinical Genetics, UCLA, Los Angeles, CA, USA., Weksberg R; Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Pediatrics, Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.; Institute of Medical Sciences, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Arboleda VA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.; Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.; Interdepartmental Bioinformatics Program, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.; Molecular Biology institute, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.
Jazyk: angličtina
Zdroj: BMC medical genomics [BMC Med Genomics] 2024 Nov 29; Vol. 17 (1), pp. 282. Date of Electronic Publication: 2024 Nov 29.
DOI: 10.1186/s12920-024-02039-7
Abstrakt: Background: Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 (ASXL1), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML.
Methods: This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1-variant (AML-ASXL1) and examined differential exon usage and cell proportions.
Results: Our analyses identified common molecular signatures between BOS and AML-ASXL1 and highlighted key biomarkers, including VANGL2, GRIK5 and GREM2, that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A (HOXA) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4. While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML-ASXL1.
Conclusion: Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.
Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approval was obtained through the Institutional Ethics Review Boards at UCLA and Hospital for Sick Children. Informed consent was obtained from all research participants according to the protocol approved by the Hospital for Sick Children (REB#1000038847) and UCLA (IRB#11-001087). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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