KMT2A (Lysine Methyltransferase 2A)

Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry. These data expanded our molecular understanding of these rare bone tumors.

P1, N=76, Active, not recruiting, Syndax Pharmaceuticals | Recruiting --> Active, not recruiting

Revumenib is a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, and it is now in clinical use for treatment of MLLr and NPM1-mutated (NPM1c) acute leukemia...Immunocompromised mice engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. These findings reveal a role for JUND in MLLr AML and suggest that targeting JUND transcription factor activity enhances the efficacy of menin-MLL inhibitors towards MLLr leukemic cells.

Patients with lineage switch have dismal outcomes and optimal therapies remain unknown, thus there is a large unmet need to better understand the biology, define the diagnosis, and determine the therapeutic approaches to lineage switch. Here, we address these needs providing a review of the current biology of lineage switch, the relationship to different genetic subtypes and present definitions and recommendations for immunophenotypic and molecular monitoring.

This case highlights the diagnostic complexity and therapeutic implications of isolated extramedullary AML relapse and underscores the need to perform genetic testing at the site of disease recurrence-especially without bone marrow involvement of relapsed disease. The authors have confirmed clinical trial registration is not needed for this submission.

Notably, expression of these modules decreased upon degradation of the leukemogenic onco-fusion proteins KMT2A::MLLT3 and PML::RARA, indicating that lincRNA expression is responsive to oncogenic signaling. This comprehensive analysis shows that lincRNAs exhibit similar subclass-specific expression patterns as protein-coding genes and establishes a valuable resource for future studies on genetically defined AML subclasses, with potential implications for biomarker discovery and therapeutic targeting.

Notably, Natalizumab (NTZ) - an FDA/EMA-approved monoclonal antibody targeting ITGA4 - delayed leukemia progression and potentiated the efficacy of standard-of-care chemotherapy in KMT2A-r B-ALL patient-derived xenograft (PDX) models. Collectively, our findings define a novel ITGA4-NG2 signaling axis that drives the aggressiveness of KMT2A-r B-ALL and support the repurpose of NTZ as an adjuvant therapeutic strategy for this high-risk leukemia subtype.

Importantly, distinct genetic lesions appear to correlate with specific immunophenotypic patterns, suggesting biologically meaningful disease subsets and providing insights into mechanisms of lineage plasticity and leukemogenesis. This review summarizes the current understanding of the immunophenotypic and genetic landscape of MPAL, emphasizing the integration of morphologic, immunophenotypic, cytogenetic, and molecular findings into diagnosis and subclassification.

HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

P2, N=300, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2027

KMT2A was significantly upregulated in intrahepatic cholangiocarcinoma and elevated H3K4me3 levels at the JAK2 promoter, leading to higher JAK2 expression and activation of the JAK2/STAT3 pathway, which, in turn, stimulated ICC cell proliferation. This study offers novel insights into the potential of KMT2A as both a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma.