The PRMT5-p53-DUSP6 Axis: Integral Regulators of Cytokine Signaling in Hematopoietic Cells and AML Oncogenesis

Acute myeloid leukemia (AML) is accepted as one of the aggressive forms of cancer that arises in the bone marrow resulting in the abnormal production of white blood cells. Despite the recent treatments, AML is still the most common type of acute leukemia in adults with a high recurrence rate. Chemotherapy, stem cell transplants, and more recently, targeted therapies center on specific genetic mutations in the cancer cells are among the therapeutic approaches for AML. Due to the presence of molecular and cytogenetic abnormalities in AML, there are mutations in critical genes of normal cell development, cellular survival, proliferation, and maturation.  These mutations form another layer to the challenges of AML treatment without inducing toxicity. Additionally, it has been observed that in almost every patient with AML, different groups of cancerous cells coexist. Each one of these subgroups is identified by a unique set of genetic and epigenetic abnormalities which may respond differently to treatment. Therefore, there is upmost need for expanding our understanding of AML’s complex molecular, cellular and clonal structure to advance the treatment of AML. From this point, studies in cytokine signaling are important for advancing our knowledge of AML because cytokines are key regulators of cell growth, survival and immune response. For example, in the context of AML, if cytokine signaling pathways become dysregulated, they could cause the uncontrolled proliferation of leukemic cells. Therefore, by unraveling how cytokine signaling pathways are dysregulated in AML progression, scientists can identify potential therapeutic targets to cut off these abnormal signals. This study will uncover unique aspects of two important genes PRMT5 and p53 and how the interactions of these two genes affect the way blood stem cells respond to chemical cytokine signals that regulate cell behavior, specifically DUSP6. Successful outcome of this study will provide information about changes in the expression levels of these two genes alter the cytokine signaling pathways focused on DUSP6 activity. For future studies, understanding how PRMT5 and p53 work separately or together to dysregulate cytokine signaling causing to promote AML could eventually lead us to new treatments. In other words, studying the effects of PRMT5 and p53 on cytokine signaling dysregulations could stop or slow the cancer’s progression, offering patients a better chance to long-term survival.