CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27kip1 signaling

Feifei Zhang, Xiaoye Liu, Chiqi Chen, Jun Zhu, Zhuo Yu, Jingjing Xie, Li Xie, Haitao Bai, Yaping Zhang, Xia Fang, Hao Gu, Chun Wang, Wei Weng, Chengcheng Zhang, Guo Qiang Chen, Aibing Liang, Junke Zheng

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Targeting leukemia initiating cells is considered to be an effective way to cure leukemia, for which it is critical to identify novel therapeutic targets. Herein, we demonstrate that CD244, which was initially reported as a key regulator for natural killer cells, is highly expressed on both mouse and human leukemia initiating cells. Upon CD244 knockdown, human leukemia cell lines and primary leukemia cells have markedly impaired proliferation abilities both in vitro and in vivo. Interestingly, the repopulation ability of both mouse and human hematopoietic stem cells is not impaired upon CD244 knockdown. Using an MLL-AF9-induced murine acute myeloid leukemia model, we show that leukemogenesis is dramatically delayed upon CD244 deletion, together with remarkably reduced Mac1+/c-Kit+ leukemia cells (enriched for leukemia initiating cells). Mechanistically, we reveal that CD244 is associated with c-Kit and p27 except for SHP-2 as previously reported. CD244 co-operates with c-Kit to activate SHP-2 signaling to dephosphorylate p27 and maintain its stability to promote leukemia development. Collectively, we provide intriguing evidence that the surface immune molecule CD244 plays an important role in the maintenance of stemness of leukemia initiating cells, but not in hematopoietic stem cells. CD244 may represent a novel therapeutic target for the treatment of acute myeloid leukemia.

Original languageEnglish (US)
Pages (from-to)707-718
Number of pages12
JournalHaematologica
Volume102
Issue number4
DOIs
StatePublished - Mar 31 2017

ASJC Scopus subject areas

  • Hematology

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    Zhang, F., Liu, X., Chen, C., Zhu, J., Yu, Z., Xie, J., Xie, L., Bai, H., Zhang, Y., Fang, X., Gu, H., Wang, C., Weng, W., Zhang, C., Chen, G. Q., Liang, A., & Zheng, J. (2017). CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27kip1 signaling. Haematologica, 102(4), 707-718. https://doi.org/10.3324/haematol.2016.151555