Therapeutic targeting of Hairy and Enhancer of Split 1 (HES1) transcriptional programs in T-cell Acute Lymphoblastic Leukemia
By: Stephanie A. Schnell
Publisher: [publisher not identified]
Published: 2015
Place of publication: [New York, N.Y.?]
Language: eng
Description: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor resulting from the malignant transformation of immature T-cell progenitors. Originally associated with a dismal prognosis, the outcome of T-ALL patients has improved remarkably over the last two decades as a result of the introduction of intensified chemotherapy protocols. However, these treatments are associated with significant acute and long-term toxicities, and the treatment of patients presenting with primary resistant disease or those relapsing after a transient response remains challenging. Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify HES1, a transcriptional repressor controlled by NOTCH1 as a critical mediator of NOTCH1 induced leukemogenesis strictly required for tumor cell survival.

Mechanistically, we demonstrate that HES1 inhibits leukemia cell death by repressing BBC3, the gene encoding the PUMA BH3-only proapototic factor. Finally, we identify perhexiline, a small molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1 induced leukemias in vitro and in vivo.
Notes: Department: Cellular, Molecular and Biomedical Studies.

Thesis advisor: Adolfo Ferrando.

Thesis (Ph.D.)--Columbia University, 2015.