A C-terminal mutant of CCAAT-enhancer-binding protein alpha (C/EBP alpha-C-m) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBP alpha-C-m

作者：Togami Katsuhiro; Kitaura Jiro; Uchida Tomoyuki; Inoue Daichi; Nishimura Koutarou; Kawabata Kimihito C; Nagase Reina; Horikawa Sayuri; Izawa Kumi; Fukuyama Tomofusa; Nakahara Fumio; Oki Toshihiko; Harada Yuka; Harada Hironori; Aburatani Hiroyuki; Kitamura Toshio^*

来源：Experimental Hematology, 2015, 43(4): 300-308.

DOI：10.1016/j.exphem.2014.11.011

Two types of CCAAT-enhancer-binding protein a (C/EBP alpha) mutants are found in acute myeloid leukemia (AML) patients: N-terminal frame-shift mutants (C/EBP alpha-N-m) generating p30 as a dominant form and C-terminal basic leucine zipper domain mutants (C/EBP alpha-C-m). We have previously shown that C/EBP alpha-K304_R323dup belonging to C/EBP alpha-C-m, but not C/EBP alpha-T6OfsX159 belonging to C/EBP alpha-N-m, alone induced AML in mouse bone marrow transplantation (BMT) models. Here we show that various C/EBP alpha-C-m mutations have a similar, but not identical, potential in myeloid leukemogenesis. Notably, like C/EBP alpha-K304_R323dup, any type of C/EBP alpha-C-m tested (C/EBP alpha-S299_K304dup, K313dup, or N321D) by itself induced AML, albeit with different latencies after BMT; C/EBP alpha-N321D induced AML with the shortest latency. By analyzing the gene expression profiles of C/EBP alpha-N321D- and mock-transduced c-kit(+)Sca-1(+)Lin(-) cells, we identified Csf1r as a gene downregulated by C/EBP alpha-N321D. In addition, leukemic cells expressing C/EBP alpha-C-m exhibited low levels of colony stimulating factor 1 receptor in mice. On the other hand, transduction with C/EBP alpha-N-m did not influence Csf1r expression in c-kit(+)Sca-1(+)Lin(-) cells, implying a unique role for C/EBP alpha-C-m in downregulating Csf1r. Importantly, Csf1r overexpression collaborated with C/EBP alpha-N321D to induce fulminant AML with leukocytosis in mouse BMT models to a greater extent than did C/EBP alpha-N321D alone. Collectively, these results suggest that C/EBP alpha-C-m-mediated downregulation of Csf1r has a negative, rather than a positive, impact on the progression of AML involving C/EBP alpha-C-m, which might possibly be accelerated by additional genetic and/or epigenetic alterations inducing Csf1r upregulation.

• 出版日期2015-4
• 单位河北医科大学