title: Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the γ-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case.
abstract: Notch pathway antagonists such as γ-secretase inhibitors (GSIs) 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 GSIs downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSIs was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T-cell type. H3K27ac super-enhancer 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: Departments of Medicine and Genetics, Stanford University, Stanford, California 95305, USA;
authors.forename: Ami
authors.initials: A
authors.lastname: Bhatt
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;; Broad Institute of MIT and Harvard University, Cambridge, Massachusetts 02142, USA;
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Eric
authors.initials: E
authors.lastname: Severson
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: David M
authors.initials: DM
authors.lastname: Dorfman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Frank C
authors.initials: FC
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Kluk
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Patrick
authors.initials: P
authors.lastname: Zweidler-McKay
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;; Broad Institute of MIT and Harvard University, Cambridge, Massachusetts 02142, USA;
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
keywords: leukemia