Venetoclax plus gilteritinib is effective in preclinical models of <i>FLT3</i> -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 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.
Authors
- Zhongshan Cheng (ORCID: https://orcid.org/0000-0002-6746-5182)
- Jamila Moore (ORCID: https://orcid.org/0009-0005-6166-944X)
- Qingsong Gao (ORCID: https://orcid.org/0000-0002-9930-8499)
- Marina Konopleva (ORCID: https://orcid.org/0000-0002-9347-2212)
- Amit Budhraja
- Torsten Haferlach (ORCID: https://orcid.org/0000-0003-0196-2837)
- Tanya Khan
- Charles Grenfell Mullighan (ORCID: https://orcid.org/0000-0002-1871-1850)
- Burgess B. Freeman (ORCID: https://orcid.org/0000-0003-2174-5119)
- Joseph T. Opferman (ORCID: https://orcid.org/0000-0002-1147-5621)
- Pradyumna Baviskar
- Ilaria Iacobucci (ORCID: https://orcid.org/0000-0003-2008-1365)
- Hongjian Jin (ORCID: https://orcid.org/0000-0003-3833-7170)
- Huimei Wei
- Lindsey E. Montefiori (ORCID: https://orcid.org/0000-0003-2342-6349)
- William C. Wright (ORCID: https://orcid.org/0000-0002-2274-9966)
- Melissa Johnson (ORCID: https://orcid.org/0000-0002-3794-3518)
- Cyrus Mehr
- Emily A. Backhaus (ORCID: https://orcid.org/0000-0002-1253-9148)
- Surbhi Sona (ORCID: https://orcid.org/0000-0002-6644-8970)
- Laura J. Janke (ORCID: https://orcid.org/0000-0002-9871-6239)
- Qi Zhang (ORCID: https://orcid.org/0000-0002-7918-8952)
- Paul E. Mead
- Josi Lott (ORCID: https://orcid.org/0009-0004-2504-8657)
Institutions
- Albert Einstein College of Medicine (US)
- St. Jude Children's Research Hospital (US)
- SUNY Downstate Health Sciences University (US)
- Munich Leukemia Laboratory (Germany) (DE)
- Woodlands Hospital (GB)
Publication Details
- Journal
- Blood
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1182/blood.2025028985
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Amgen
- Pfizer
- Leukemia and Lymphoma Society
- St. Jude Children's Research Hospital
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Cancer Institute