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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

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 Knoechel, Ami Bhatt, Li Pan, Chandra S Pedamallu, Eric Severson, Alejandro Gutierrez, David M Dorfman, Frank C Kuo, Michael Kluk, Andrew L Kung, Patrick Zweidler-McKay, Matthew Meyerson, Stephen C Blacklow, etc.

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

PMID: 27148573

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1401066792	BMS-906024		1401066-79-2	Price

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