The deubiquitylase USP22 (Ubiquitin Specific Peptidase 22) is highly expressed in Acute Myeloid Leukemia (AML) and T-Acute Lymphoblastic Leukemia (T-ALL). Moreover, additional studies showed that human AML samples with mutations in an upstream activator of Ras signaling expressed the highest levels of USP22. Studies in vitro have shown that USP22 is required for the transition from self-renewal to differentiation in embryonic stem cells, is necessary for the transcription of c-Myc target genes and its germ line deletion is lethal. However, the function of USP22 in leukemogenesis is unknown. The long term of goal of this project is to understand the function of USP22 in cancer. Reason for which, our lab generated the first conditional mouse model of Usp22. Preliminary observations using a mouse model of myeloproliferative neoplasm and T-ALL (MPN/T-ALL) induced by Ras, showed that contrary to what was expected, Usp22 genetic deletion did not improve mice survival. These mice presented non-hematological tumors that impeded further studies on the function of Usp22 using this mouse model. For this proposal, a different mouse model that develops only myeloid malignances ?Acute Myeloid Leukemia (AML) driven by MLL-AF9? will be used for studying the function of Usp22. Based on the data obtained using the MPN/T-ALL mouse model, the central hypothesis for this study is that Usp22 mediates hematopoietic differentiation and its absence increases the accumulation of early stage progenitors under oncogenic conditions. This hypothesis will be addressed in two aims.
The first aim will focus on studying the phenotype and cellular mechanisms by which Usp22 deletion will accelerate MLL-AF9?driven AML.
The second aim will address the molecular mechanisms involving Usp22 transcriptional regulation of Myc in AML. The methods that will be used to accomplish the proposed aims include novel transgenic mouse models, genome wide RNA sequencing, molecular biology assays and biochemistry techniques. The studies proposed in this project will provide fundamental insights into the in vivo functions of USP22 in myeloid malignances. It will also result in the discovery of novel molecular mechanisms underlying leukemogenesis. In future studies, we will study the function of USP22 in other blood malignances such as T- Acute Lymphoblastic leukemia, in which USP22 is also highly expressed.
Usp22, a cellular protein, has been shown to be present at high levels in leukemia. However, little is known on how Usp22 function affects the generation of leukemia. This project will define Usp22 function in the development of one type of leukemia (Acute Myeloid Leukemia) and will provide new fundamental insights on understanding the specific roles that Usp22 play in leukemia.
|Melo-Cardenas, Johanna; Xu, Yuanming; Wei, Juncheng et al. (2018) USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism. Blood 132:423-434|