Necdin modulates leukemia-initiating cell quiescence and chemotherapy response

Chonghua Yao, Michihiro Kobayashi, Sisi Chen, Sarah C. Nabinger, Rui Gao, Stephen Z. Liu, Takashi Asai, Yan Liu

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)87607-87622
Number of pages16
JournalOncotarget
Volume8
Issue number50
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Chemotherapy
  • Leukemia-initiating cells
  • MLL-AF9
  • Necdin
  • Quiescence

ASJC Scopus subject areas

  • Oncology

Cite this

Yao, C., Kobayashi, M., Chen, S., Nabinger, S. C., Gao, R., Liu, S. Z., Asai, T., & Liu, Y. (2017). Necdin modulates leukemia-initiating cell quiescence and chemotherapy response. Oncotarget, 8(50), 87607-87622. https://doi.org/10.18632/oncotarget.20999