Dual inhibition of FLT3 and BCL-2 is effective in preclinical models of BCL11B-activated 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. As with other lineage ambiguous leukemias, optimal treatment is unclear and there are limited targeted therapeutic options. Here, we investigated the efficacy of BCL-2 and 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 was highly effective in all models evaluated. BH3 profiling and single cell RNA-seq analysis suggests that resistance to venetoclax and/or gilteritinib monotherapies is due to the tumor-intrinsic activity of BCL-xL and/or MCL-1 prior to drug treatment. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias.

Type: Cancer Genomics
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD50000001424	This dataset includes single cell (sc)RNA-seq of N=3 patient-derived xenograft (PDX) samples profiled at baseline (no drug treatment) and N=12 samples from one PDX profiled during the course of treatment (N=1 sample each for 4 treatment arms x 3 timepoints). The dataset includes bam files that have been purged of reads mapping to cells where a majority of the reads from that cell mapped to the mouse genome. All scRNA-seq data were generated using the Chromium Next GEM Single Cell 5' Reagent Kits v2 (Dual Index) from 10X Genomics.	Illumina NovaSeq 6000	15
EGAD50000001425	This dataset includes whole exome sequencing (WES) data from PDX samples post-drug treatment (N=1 vehicle, N=1 gilteritinib, N=1 venetoclax and N=1 VenGilt). Bam files are provided for each sample. The VenGilt-treated sample underwent whole genome amplification using the Qiagen REPLI-g kit (#150345) prior to sequencing due to the very low cell number.	Illumina HiSeq 2500	4

Publications	Citations
Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia. Montefiori LE, Iacobucci I, Gao Q, Moore J, Wright WC, Wei H, Baviskar P, Sona S, Jin H, Budhraja A, Lott J, Tatarata QZ, Cheng Z, Khan T, Backhaus Wagner EA, Johnson M, Mehr CM, Freeman B, Janke L, Haferlach T, Geeleher P, Mead PE, Konopleva M, Opferman JT, Mullighan CG. Blood 146: 2025 2350-2356	0

Publications

Citations

Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.
Montefiori LE, Iacobucci I, Gao Q, Moore J, Wright WC, Wei H, Baviskar P, Sona S, Jin H, Budhraja A, Lott J, Tatarata QZ, Cheng Z, Khan T, Backhaus Wagner EA, Johnson M, Mehr CM, Freeman B, Janke L, Haferlach T, Geeleher P, Mead PE, Konopleva M, Opferman JT, Mullighan CG. Blood 146: 2025 2350-2356