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From Molecular Case Studies: Genomics of exceptional responder to NOTCH inhibitor

Cold Spring Harbor Laboratory


IMAGE: This is a histology staining of patient's bone marrow before (left), and after 4 weeks (middle) and 7 weeks (right) of treatment. The marrow contains mainly leukemic blasts prior to... view more

Credit: Copyright Knoechel et al.

Normal T-cell development requires Notch signaling but hyperactivity can lead to cancer. Drugs that inhibit Notch, such as gamma-secretase inhibitors (GSIs), are currently being tested in different cancer types but clinical remission has yet to be reported. In a paper published in Cold Spring Harbor Molecular Case Studies, researchers describe an acute lymphoblastic leukemia (ALL) patient in which GSI treatment resulted in complete remission, suggesting that GSIs may hold therapeutic promise in ALL and other cancers.

The patient, a 53-yr-old male diagnosed with early T-cell precursor leukemia (ETP-ALL), was not responding to previous rounds of chemotherapy. At relapse, he was seen by physicians at Dana-Farber Cancer Institute and was enrolled in a clinical trial for the Notch inhibitor BMS-906024. He began to show immediate improvement and after three cycles of treatment received a blood stem cell transplant, and since has been cancer free for 19 months.

To determine the genetic basis for his exceptional response, researchers at the Dana-Farber Cancer Institute, Stanford University, Brigham and Women's Hospital and elsewhere performed targeted and whole-exome sequencing on his leukemic cells. They identified four potential mutations driving the cancer progression, including a novel mutation in the NOTCH1 gene resulting in hyperactive signaling. This mutated gene copy was also duplicated in the cancer genome, resulting in elevated expression. After treatment with GSI, the NOTCH1 mutation, along with two of the other mutations, were absent in the remission bone marrow.

Furthermore, the authors cultured the patient's leukemic cells to determine the molecular response to GSI treatment. Cells treated with GSI had greatly reduced levels of mutated NOTCH1 protein. RNA-seq analysis demonstrated that Notch target genes were sensitive to the treatment. Interestingly, however, a common oncogenic gene, MYC, was not sensitive to GSI. Epigenetic analysis determined that the enhancer driving MYC expression in the leukemic cells was not Notch-dependent, but rather BRD4-dependent, suggesting another possible therapeutic option for MYC-expressing tumors.


Media Contacts:

The authors are available for more information by contacting: Haley Bridger, Senior Science Communication Specialist, Communication & Public Affairs, Brigham and Women's Hospital (, cell: 978-807-5302, office: 617-525-6383)

Interested reporters may obtain copies of the manuscript online at our website: or via email from Peggy Calicchia, Administrative Assistant (, +1-516-422-4012)

About the article:

The manuscript will appear in the October issue of CSH Molecular Case Studies. Its full citation is as follows: Knoechel B, Bhatt A, Pan L, Pedamallu CS, Severson E, Gutierrez A, Dorfman DM, Kuo FC, Kluk M, Kung AL, Zweidler-McKay P, Meyerson M, Blacklow SC, DeAngelo DJ, Aster JC. 2015. 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 1: a000539.

About Cold Spring Harbor Molecular Case Studies:

Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal's purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. Since 1933, it has furthered the advance and spread of scientific knowledge in all areas of genetics and molecular biology, including cancer biology, plant science, bioinformatics, and neurobiology. The Press is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit our website at

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