Menin Inhibitors: New Targeted Therapies for Specific Genetic Subtypes of Difficult-to-Treat Acute Leukemias

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

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Is Enhancer Function Driven by Protein–Protein Interactions? From Bacteria to Leukemia

BioEssays, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

ABSTRACT The precise regulation of the transcription genes is essential for normal development and maintenance life. Aberrant gene expression changes drive many human diseases. Despite this, we still do not completely understand how controlled in living systems. Enhancers are key regulatory elements that enable cells to specifically activate response environmental cues, or a stage tissue‐specific manner. Any model enhancer activity needs answer two main questions: (1) enhancers able identify act on specific (2) influence transcription. To address these points, first outline some basic principles can be established from simpler prokaryotic systems, then discuss recent work aberrant leukemia. We argue highly protein–protein interactions driver enhancer‐promoter proximity, allowing enhancer‐bound factors directly RNA polymerase

Language: Английский

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Recent Developments and Evolving Therapeutic Strategies in KMT2A‐Rearranged Acute Leukemia

Cancer Medicine, Journal Year: 2024, Volume and Issue: 13(20)

Published: Oct. 1, 2024

ABSTRACT Background Rearrangements of the histone‐lysine‐N‐methyltransferase (KMT2A) , previously referred to as mixed‐lineage leukemia (MLL), are among most common chromosomal abnormalities in patients with acute myeloid (AML) and lymphoblastic (ALL), involving numerous different fusion partners. KMT2A ‐rearranged ( ‐r) is characterized by a rapid onset, aggressive progression, significantly worse prognosis compared non‐ ‐r leukemias. Even contemporary chemotherapeutic treatments hematopoietic stem cell transplantations (HSCT), typically experience poor outcomes limited responses these therapies. Objectives This review aims consolidate recent studies on general gene characteristics associated mechanisms KMT2A‐ r leukemia, well cytogenetics, immunophenotype, clinical presentation, risk stratification both r‐AML ‐r‐ALL. Particularly, treatment targets examined. Methods A comprehensive was carried out systematically synthesizing existing literature PubMed, using combination keywords ‘ leukemia’, ‘lymphoblastic ‘myeloid ‘therapy’. The available were screened for selection based quality relevance. Conclusions Studies indicate that rearrangements present over 70% infant cases, approximately 10% adult AML instances secondary leukemias, making it disease critical concern clinicians researchers alike. future research an expanding knowledge disease's biology, emphasis personalized therapies, immunotherapies, genomic advancements, innovative therapeutic combinations. overarching aim enhance patient outcomes, lessen burden, elevate life those affected. Ongoing trials this area continue offer promising opportunities refining strategies improving prognosis.

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Abstract Genetic alterations alone cannot account for the diverse phenotypes of cancer cells. Even cancers with same driver mutation show significant transcriptional heterogeneity and varied responses to therapy. However, mechanisms underpinning this 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 poor prognosis low mutational burden, exhibits substantial between individuals. Using single cell multiome analysis extensive chromatin profiling, reveal much ALL driven by usage. high resolution Micro-Capture-C primary patient samples, also identify patient-specific activity at key oncogenes such as MEIS1 RUNX2 , driving levels expression both manner. Overall, our data highly prevalent may be mechanism drives more generally. Key Points Leukemia patients mutations often display gene differences profiling 3C methods

Language: Английский

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Editorial overview: Breaking boundaries: new frontiers in chromatin regulation for cancer therapy

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 88, P. 102255 - 102255

Published: Sept. 3, 2024

Language: Английский

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