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
- Birgit Knoechel1,9,
- Ami Bhatt2,9,
- Li Pan3,
- Chandra S. Pedamallu1,4,
- Eric Severson3,
- Alejandro Gutierrez5,
- David M. Dorfman3,
- Frank C. Kuo3,
- Michael Kluk3,
- Andrew L. Kung6,
- Patrick Zweidler-McKay7,
- Matthew Meyerson1,3,4,
- Stephen C. Blacklow8,
- Daniel J. DeAngelo1 and
- Jon C. Aster3
- 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
- 2Departments of Medicine and Genetics, Stanford University, Stanford, California 95305, USA;
- 3Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
- 4Broad Institute of MIT and Harvard University, Cambridge, Massachusetts 02142, USA;
- 5Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 6Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;
- 7Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 8Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
- Corresponding author: jaster{at}partners.org
-
↵9 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
- Received June 27, 2015.
- Accepted July 25, 2015.
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