BioProject

Notch pathway antagonists such as gamma-secretase inhibitors (GSI) are being tested in diverse cancers, but exceptional responses have yet to be reported. More...

Notch pathway antagonists such as gamma-secretase inhibitors (GSI) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early-T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient’s ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-Seq documented that GSI downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSI was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T cell type. H3K27ac superenhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited. Overall design: RNAseq and H3K27Ac ChIP seq of primary leukemic blasts treated in vitro with vehicle control or gamma-secretase inhibitor BMS-096024 Less...