Despite advancements in standard chemotherapy regimens, acute lymphoblastic leukemia is still the leading cause of cancer death in children. Patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL) have a particularly grim prognosis, and survivors develop long-term disabilities such as cognitive dysfunction and secondary cancers. Activating mutations in NOTCH1 have been implicated in more than 60% of patient T- cell acute lymphoblastic leukemias (T-ALL), giving hope for a targeted therapy in this disease. However, enthusiasm for pan-Notch inhibitors has been tempered by clinical trials showing that broad inhibition of Notch1 signaling results in treatment-limiting toxicities. The Notch signaling pathway is seemingly simple: ligand from a neighboring cell triggers proteolytic cleavage of the intracellular domain from the recipient cell's membrane. The intracellular domain is then free to translocate to the nucleus, where it associates with other cofactors to induce transcription of target genes involved in cellular growth and cell fate decisions. However, Notch signaling serves disparate functions in different tissues, even acting as an oncogene in some cancers while a tumor suppressor in others. What contributes to this pleotropic nature of Notch? A major contributor is the nuclear context. In T-ALL, Notch1 signaling promotes leukemic cell growth primarily through its activity at T-cell specific enhancers, which increase transcription of oncogenes, particularly MYC. Notch1 cannot activate these enhancers by itself; it requires other transcription factors to create a cell-type specific nuclear context that directs Notch1 to function. In theory, one could target the specific nuclear context that drives Notch in T- ALL in order to avoid the intolerable effects of pan-Notch inhibition. One factor that may promote T-cell specific Notch1 activity is Ets1. Ets1 is a highly conserved transcription factor involved in T-cell, B-cell, and NK-cell development. It has much more limited roles in normal tissue homeostasis than Notch. It is broadly and highly expressed in T-ALL and binds most Notch1-driven enhancers in a T-ALL cell line. This proposal's central hypothesis is that Ets1 drives the proliferation of T-ALL cells by enhancing Notch1 activity at oncogenic target genes.
The first aim of the project utilizes primary human patient samples and mouse models of T-ALL to determine whether inhibition of Ets1 can safely and effectively treat T-ALL.
The second aim of the project will use biochemical and genomic sequencing approaches to clarify the mechanism by which Ets1 enhances Notch1 target gene transcription. This proposal seeks to establish the potential of Ets1 inhibition as a therapeutic strategy for T-ALL, to identify the protein- protein interfaces required for the Ets1-Notch1 interaction, and to assess the impact of Ets1 loss on Notch1's recruitment to DNA, epigenetic modifications, and target gene transcription. By targeting the specific interactions responsible for oncogenic, context-dependent Notch1 signaling, it might be possible to inhibit Notch1 in cancer without the toxicity of pan-Notch inhibition.

Public Health Relevance

Activating mutations in NOTCH1 have been implicated in more than 60% of patient T-cell acute lymphoblastic leukemias (T-ALL); however, broad inhibition of Notch1 signaling results in treatment-limiting toxicities. Identifying cofactors important for Notch1's context-dependent transcriptional activity in the nucleus might provide new, safer targets for therapeutics. The proposed research is relevant to public health because it would identify a druggable target for T-ALL therapeutics, as well as a novel strategy for combating Notch signaling in cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Wang, Qing; Yan, Ran; Pinnell, Nancy et al. (2018) Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development. Blood 132:1279-1292