Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000539. doi: 10.1101/mcs.a000539.

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.

Knoechel B¹, Bhatt A², Pan L³, Pedamallu CS⁴, Severson E³, Gutierrez A⁵, Dorfman DM³, Kuo FC³, Kluk M³, Kung AL⁶, Zweidler-McKay P⁷, Meyerson M⁸, Blacklow SC⁹, DeAngelo DJ¹, Aster JC³.

Author information

1: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
2: Departments of Medicine and Genetics, Stanford University, Stanford, California 95305, USA;
3: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
4: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;; Broad Institute of MIT and Harvard University, Cambridge, Massachusetts 02142, USA;
5: Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
6: Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;
7: Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
8: 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;
9: Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

KEYWORDS:

leukemia

PMID:: 27148573
PMCID:: PMC4850884
DOI:: 10.1101/mcs.a000539

Free PMC Article

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Figure 2.

Characterization of the NOTCH1 gain-of-function mutation F1592C. (A) Position of F1592C in the NOTCH1 negative regulatory region (NRR). Mapping is based on the crystallographic structure of Gordon et al. (). Residues previously reported be mutated in T-ALL are shown in green (core residues), orange (interdomain interface residues), or purple (polar residues). The three LNR repeats are colored various shades of pink with a translucent surface, and the core “heterodimerization domain” is colored blue prior to the site of furin cleavage (HD-N) and cyan thereafter (HD-C). F1592 sits in the center of the hydrophobic core of the heterodimerization domain. The image is rendered with the program Pymol and is adapted from Gordon et al. (). (B) F1592C leads to ligand-independent activation of NOTCH1. The ability of the F1592C variant to activate a Notch firefly luciferase reporter gene was compared with wild-type NOTCH1 and two previously characterized gain-of-function mutants, F1592S and L1593P. Firefly luciferase activity was normalized to an internal Renilla luciferase control reporter gene. Normalized firefly luciferase activity is expressed related to the activity of wild-type NOTCH1, which is arbitrarily set to a value of 1. Each expression plasmid was tested in three independent experiments; error bars represent the standard deviations. (C) Copy-number gains and losses. The copy number of chromosomal regions was determined from sequencing data as described (). (D) Effect of the GSI diaminobenzidine (DBZ) on activated NOTCH1 (ICN1) levels in leukemic blasts. Blasts were treated with vehicle (DMSO [dimethyl sulfoxide]) or DBZ for 3 d prior to harvest and preparation of whole-cell lysates. A representative Western blot stained for activated NOTCH1 (ICN1) and β-actin is shown.

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

Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000539.