Investigating the role of miR-155 and the interferon response in FLT3-ITD+ AML

University Of Utah, Salt Lake City UT

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Abstract

PROJECT SUMMARY/ABSTRACT Acute Myeloid Leukemia (AML) is a life-threatening disease that leads to the death of over 10,000 people in the United States each year. AML is a hematologic malignancy characterized by the overproduction of cancerous blast cells in the bone marrow, which ultimately results in bone marrow failure. This disruption in normal hematopoiesis leads to life-threatening conditions, including anemia, immunosuppression, and bleeding. Approximately one-third of AMLs are associated with a gain of function mutation known as internal tandem duplication (ITD) in FMS-like tyrosine kinase 3 (FLT3), a cell surface receptor needed for cellular proliferation and survival in the hematopoietic stem and progenitor cell compartment. Patients diagnosed with FLT3-ITD+ AML have a particularly poor prognosis. However, FLT3-ITD is not sufficient to cause AML. FLT3- ITD has been reported to cause a myeloproliferative disease (MPD) in mice, and it is thought that additional mutations are needed to collaborate with FLT3-ITD in order to cause leukemic transformation. MicroRNAs are a class of non-coding RNAs that have been shown to play a variety of roles in the hematopoietic compartment and in hematopoietic malignancy. MicroRNAs repress their mRNA targets by binding to the 3'UTR of the mature transcript, preventing downstream translation. MiR-155, a particular microRNA, has recently been shown to be specifically overexpressed in FLT3-ITD+ AMLs, but the mechanism underlying this association remains unclear. Overexpression of miR-155 in the hematopoietic compartment has previously been reported to cause the development of MPD in mice. In this study, we aim to define the role of miR-155 in FLT3-ITD+ AML. Through loss of function studies in genetic mouse models, we will determine whether miR-155 and FLT3- ITD collaborate in order to lead to disease progression. We will utilize bone marrow reconstitution experiments in mice to determine if FLT3-ITD combined with miR-155 overexpression can cause leukemic transformation. We will also test whether miR-155 is needed for FLT3-ITD to collaborate with other oncogenic mutations to induce leukemic transformation. These model systems will also allow us to determine the downstream effects of miR-155 expression in FLT3-ITD. Hematopoietic progenitors are under constant guidance of exogenous cytokines in the bone marrow, and both type I and II interferon are known to have an anti-proliferative effect on hematopoietic cells. We believe that miR-155 could be promoting the growth of FLT3-ITD progenitors through inhibiting interferon responses in these cells. The results of this study could provide evidence to support targeting miR-155 to treat FLT3-ITD+ AML.