Venetoclax plus gilteritinib is effective in preclinical models of FLT3 -mutant BCL11B-a lineage-ambiguous leukemia
Year: 2025
Type: article
Abstract: ABSTRACT: 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.
Source: Blood
Authors: Lindsey E. Montefiori, Ilaria Iacobucci, Qingsong Gao, Jamila Moore, William C. Wright, Huimei Wei, Pradyumna Baviskar, Surbhi Sona, Hongjian Jin, Amit Budhraja, Josi Lott, Qi Zhang Tatarata, Zhongshan Cheng, Tanya Khan, Emily A. Backhaus Wagner, Melissa Johnson, Cyrus M. Mehr, Burgess Freeman, Laura Janke, Torsten Haferlach, Paul Geeleher, Paul E. Mead, Marina Konopleva, Joseph T. Opferman, Charles G. Mullighan
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
OpenAlex ID: W4413139415