Abstract
Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.
Highlights
Acute myeloid leukemia (AML) is the most common acute leukemia in adults
While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in leukemia-initiating cells (LICs) quiescence and response to chemotherapy are unclear
We discovered that loss of Necdin decreased the quiescence of MLL-AF9+ LICs and sensitized leukemia cells expressing MLL-AF9 to chemotherapy treatment
Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. It usually occurs around age 60 with no identifiable cause and it carries a very poor prognosis, with most patients living less than 18 months [1]. Leukemia relapse may occur because current therapies eliminate proliferating cells (that constitute the bulk of the disease) but fail to eradicate dormant leukemiainitiating cells (LICs) that can reinitiate the disease after a period of latency (the duration of remission) [1,2]. The development of new therapeutic approaches that can target LICs will have a profound impact on our ability to eradicate leukemia [8,9,10].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have