Abstract 997: Loss of Miz-1 increases latency of T-ALL by preventing induction of autophagy

The Myc-Interacting Zinc-finger protein-1 (Miz-1) can bind to the proto-oncogene c-Myc and the Miz-1/c-Myc complex can regulate the transcription of specific target genes. Miz-1 contains a BTB/POZ domain and thirteen zinc finger domains that mediate binding to DNA and its interaction with partner proteins. While Miz-1 itself functions as a transcriptional transactivator, it enables c-Myc to act as a transcriptional repressor of genes negatively regulating cell cycle progression. We have previously reported that Miz-1 plays an essential role during early stages of T cell development by regulating the translation of p53 via the ribosomal protein L22. Based on this function of Miz-1 in T cell development, we have decided to investigate a potential role of Miz-1 in the development of T cell leukemia or lymphoma. We have used several different experimental models to induce T-ALL in mice that are conditionally deficient for Miz-1. We used non-acute transforming retroviruses, such as Moloney Murine Leukemia Virus (MMLV), which induces T-cell leukemia by activating known oncogenes, including Gfi1, Pim1 and c-Myc via proviral insertion. We also used ENU mutagenesis, which induces T-cell leukemia through activation of the Ras pathway. We observed that Miz-1 is required for the development of T cell leukemia regardless of whether it is induced by MMLV or ENU, since Miz-1-deficient mice succumb to the disease with a significantly longer latency period than WT animals. Importantly, during tumorigenesis a strong counter selection occurs against the loss of Miz-1. Interestingly, MycV394D transgenic animals, carrying a c-Myc protein that can no longer interact directly with Miz-1, develop tumors at a rate comparable to WT mice, indicating that a function of Miz-1 is required for T cell tumorigenesis that is independent of its interaction with c-Myc. Transcriptome analyses showed that Miz-1 deficiency correlated with a decrease of expression in autophagy-related genes, consistent with earlier reports that Miz-1 is necessary for the induction of this pathway. ChIP-seq confirmed that Miz-1 binds to the promoters of these autophagy-related genes, indicating that these genes are activated in the presence of Miz-1, also consistent with previous reports. Furthermore, Miz-1-deficient tumors undergo higher levels of apoptosis than WT tumors. Based on these results, we conclude that Miz-1 is essential for the efficient development of T-ALL and that loss of Miz-1 significantly hinders T-ALL development in part through the inability of these cells to induce autophagy. Citation Format: Marissa Rashkovan, Charles Vadnais, Julie Ross, Jennifer Fraszczak, Tarik Moroy. Loss of Miz-1 increases latency of T-ALL by preventing induction of autophagy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 997. doi:10.1158/1538-7445.AM2015-997