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Therapeutic targeting of Hairy and Enhancer of Split 1 (HES1) transcriptional programs in T-cell Acute Lymphoblastic Leukemia

Schnell, Stephanie A.

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.

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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Ferrando, Adolfo
Degree
Ph.D., Columbia University
Published Here
June 4, 2015