Venetoclax plus gilteritinib is effective in preclinical models of <i>FLT3</i> -mutant BCL11B-a lineage-ambiguous leukemia
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.
Article Details
Authors (25)
Lindsey E. Montefiori
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Ilaria Iacobucci
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Qingsong Gao
2Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Jamila Moore
2Preclinical Therapeutics Program, St. Jude Children’s Research Hospital, Memphis, TN
William C. Wright
Huimei Wei
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Pradyumna Baviskar
1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Surbhi Sona
4Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN
Hongjian Jin
Amit Budhraja
5Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN
Josi Lott
6Center of Excellence for Leukemia Studies, St. Jude Children’s Research Hospital, Memphis, TN
Qi Zhang Tatarata
7Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY
Zhongshan Cheng
Tanya Khan
1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Emily A. Backhaus Wagner
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
Melissa Johnson
Sarah Cannon Research Institute, Nashville
Cyrus M. Mehr
1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Burgess Freeman
Laura Janke
10Comparative Pathology Core, St. Jude Children’s Research Hospital, Memphis, TN
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
Paul Geeleher
Paul E. Mead
1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
Marina Konopleva
Joseph T. Opferman
5Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN
Charles G. Mullighan