Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia

Aberrant activation of BCL11B (BCL11B-a) defines a subtype of lineage-ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. Similar to other lineage-ambiguous leukemias, optimal treatment i...

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Veröffentlicht in:Blood Jg. 146; H. 19; S. 2350
Hauptverfasser: Montefiori, Lindsey E, Iacobucci, Ilaria, Gao, Qingsong, Moore, Jamila, Wright, William C, Wei, Huimei, Baviskar, Pradyumna, Sona, Surbhi, Jin, Hongjian, Budhraja, Amit, Lott, Josi, Tatarata, Qi Zhang, Cheng, Zhongshan, Khan, Tanya, Backhaus Wagner, Emily A, Johnson, Melissa, Mehr, Cyrus M, Freeman, Burgess, Janke, Laura, Haferlach, Torsten, Geeleher, Paul, Mead, Paul E, Konopleva, Marina, Opferman, Joseph T, Mullighan, Charles G
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 06.11.2025
Schlagworte:
Aniline Compounds - administration & dosage
Aniline Compounds - pharmacology
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Bridged Bicyclo Compounds, Heterocyclic - administration & dosage
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Cell Line, Tumor
Female
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
fms-Like Tyrosine Kinase 3 - genetics
Humans
Leukemia - drug therapy
Leukemia - genetics
Leukemia - pathology
Mice
Mutation
Proto-Oncogene Proteins c-bcl-2 - genetics
Pyrazines - administration & dosage
Pyrazines - pharmacology
Sulfonamides - administration & dosage
Sulfonamides - pharmacology
Xenograft Model Antitumor Assays
ISSN:1528-0020, 1528-0020
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Zusammenfassung:Aberrant activation of BCL11B (BCL11B-a) defines a subtype of lineage-ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. Similar to other lineage-ambiguous leukemias, optimal treatment is unclear, and there are limited targeted therapeutic options. Here, we investigated the efficacy of B-cell lymphoma 2 (BCL-2) and FMS-like tyrosine kinase 3 (FLT3) inhibition with venetoclax and gilteritinib, respectively, in preclinical models of BCL11B-a leukemia. Despite variation in response to single-agent therapies, the combination of venetoclax plus gilteritinib (VenGilt) was highly effective in all models evaluated. BH3 profiling suggested that resistance to venetoclax monotherapy was due to the tumor-intrinsic dependence on additional BCL-2 family proteins before drug treatment. Longitudinal single-cell RNA sequencing analysis identified mitochondrial pathways and a pro-lymphoid gene expression signature as potential drivers of rare cell survival on VenGilt therapy. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage-ambiguous leukemias.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1528-0020
1528-0020
DOI:10.1182/blood.2025028985