Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12 DOI Creative Commons
Selina Troester, Thomas Eder,

Nadja Wukowits

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 19, 2025

Abstract Nucleoporin 98 (NUP98) fusion oncoproteins are strong drivers of pediatric acute myeloid leukemia (AML) with poor prognosis. Here we show that NUP98 fusion-expressing AML harbors an epigenetic signature is characterized by increased accessibility hematopoietic stem cell genes and enrichment activating histone marks. We employ model for ligand-induced degradation the NUP98::KDM5A oncoprotein to identify programs transcriptional targets directly regulated through CUT&Tag nascent RNA-seq. Orthogonal genome-wide CRISPR/Cas9 screening identifies 12 direct target genes, which essential growth. Among these, validate cyclin-dependent kinase (CDK12) as a druggable vulnerability in NUP98::KDM5A-expressing AML. In line its role transcription DNA damage repair small-molecule-mediated CDK12 inactivation causes damage, leading death. Altogether, regulates core set reveal actionable oncogenic fusions.

Language: Английский

Menin Inhibitors: New Targeted Therapies for Specific Genetic Subtypes of Difficult-to-Treat Acute Leukemias DOI Open Access
Pasquale Niscola, Valentina Gianfelici, Marco Giovannini

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(1), P. 142 - 142

Published: Jan. 4, 2025

Menin (MEN1) is a well-recognized powerful tumor promoter in acute leukemias (AL) with KMT2A rearrangements (KMT2Ar, also known as MLL) and mutant nucleophosmin 1 (NPM1m) myeloid leukemia (AML). MEN1 essential for sustaining leukemic transformation due to its interaction wild-type fusion proteins, leading the dysregulation of target genes. inhibitors (MIs), such revumenib, ziftomenib, other active small molecules, represent promising new class therapies currently under clinical development. By disrupting MEN1-KMT2Ar complex, group proteins involved chromatin remodeling, MIs induce apoptosis differentiation AL expressing KMT2Ar or NPM1m AML. Phase I II trials have evaluated standalone treatments combined them synergistic drugs, yielding results. These demonstrated notable response rates manageable toxicities. Among MIs, ziftomenib received orphan drug breakthrough therapy designations from European Medicines Agency January 2024 Food Drug Administration (FDA) April 2024, respectively, treating R/R patients Additionally, November FDA approved revumenib KMT2Ar-AL. This review focuses on pathophysiology MI-sensitive AL, primarily It illustrates data discusses emergence resistance mechanisms. In addition, we outline future directions use emphasize need further research fully realize potential these novel compounds, especially context specific genetic subtypes challenging AL.

Language: Английский

Citations

1
MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter DOI Creative Commons

Marius Hyprath,

Maximilian Molitor,

Ilona Schweighöfer

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 14, 2025

5-Lipoxygenase (5-LO), encoded by the gene ALOX5 , is implicated in several pathologies. As key enzyme leukotriene biosynthesis, 5-LO plays a central role inflammatory diseases, but pathway has also been linked to development of certain hematological and solid tumor malignancies. Of note, previous studies have shown that leukemogenic fusion protein MLL-AF4 strongly increases promoter activity. Here, we investigate upregulation expression MLL-AF4. Using reporter assays, first identified tandem GC box within promotor sequence as main target Subsequently, narrowed down domains responsible for activation. Our findings indicate binds via its CXXC domain AF9ID, pSER CHD redundantly activate transcriptional elongation. Knockdown human B cell line SEM revealed an inducer leukemic cells with lymphoid properties. Finally, found MLL-AF4-related MLL-AF9, driver acute myeloid leukemia, similarly acts on promoter. Taken together, show two prominent MLL proteins are inducers features.

Language: Английский

Citations

0
False positive NUP98 Fluorescence In Situ Hybridization Rearrangements in B-Acute Lymphoblastic Leukemia DOI Creative Commons

Marie-France Gagnon,

Sahil Tonk,

Benjamin Carcamo

et al.

Cancer Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Recent Developments in Differentiation Therapy of Acute Myeloid Leukemia DOI Open Access
Ugo Testa, Germana Castelli, Elvira Pelosi

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1141 - 1141

Published: March 28, 2025

Acute myeloid leukemia (AML) is characterized by the clonal expansion of progenitors blocked at various stages their differentiation process, and drugs that bypass this block are therapeutically efficient, as shown retinoic acid arsenic trioxide in acute promyelocytic leukemia. However, successful application therapy APL has not translated into clinical benefit for other non-APL subtypes AML, which intensive chemotherapy regimens represent standard care. development molecular studies led to identification therapeutic targets (such mutated proteins deregulated pathways) generation a new category specific pharmacologic agents. Some these agents, such inhibitors mutant isocitrate dehydrogenase (IDH1 IDH2), lysine-specific demethylase-1 (LSD1), Menin, have capacity induce leukemic cell with significant efficacy.

Language: Английский

Citations

0
Novel NUP98:TNRC18 fusion transcript in acute myeloid leukemia: a case report and literature review DOI Creative Commons
Lijuan Gao, Fenghong Zhang, Lijun Wen

et al.

Blood Science, Journal Year: 2025, Volume and Issue: 7(2), P. e00232 - e00232

Published: April 18, 2025

Language: Английский

Citations

0
Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12 DOI Creative Commons
Selina Troester, Thomas Eder,

Nadja Wukowits

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 19, 2025

Abstract Nucleoporin 98 (NUP98) fusion oncoproteins are strong drivers of pediatric acute myeloid leukemia (AML) with poor prognosis. Here we show that NUP98 fusion-expressing AML harbors an epigenetic signature is characterized by increased accessibility hematopoietic stem cell genes and enrichment activating histone marks. We employ model for ligand-induced degradation the NUP98::KDM5A oncoprotein to identify programs transcriptional targets directly regulated through CUT&Tag nascent RNA-seq. Orthogonal genome-wide CRISPR/Cas9 screening identifies 12 direct target genes, which essential growth. Among these, validate cyclin-dependent kinase (CDK12) as a druggable vulnerability in NUP98::KDM5A-expressing AML. In line its role transcription DNA damage repair small-molecule-mediated CDK12 inactivation causes damage, leading death. Altogether, regulates core set reveal actionable oncogenic fusions.

Language: Английский

Citations

0