Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Experimental hematology, 2015-04, Vol.43 (4), p.300-308.e1

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Two types of CCAAT-enhancer-binding protein α (C/EBPα) mutants are found in acute myeloid leukemia (AML) patients: N-terminal frame-shift mutants (C/EBPα-Nm ) generating p30 as a dominant form and C-terminal basic leucine zipper domain mutants (C/EBPα-Cm ). We have previously shown that C/EBPα-K304_R323dup belonging to C/EBPα-Cm , but not C/EBPα-T60fsX159 belonging to C/EBPα-Nm , alone induced AML in mouse bone marrow transplantation (BMT) models. Here we show that various C/EBPα-Cm mutations have a similar, but not identical, potential in myeloid leukemogenesis. Notably, like C/EBPα-K304_R323dup, any type of C/EBPα-Cm tested (C/EBPα-S299_K304dup, K313dup, or N321D) by itself induced AML, albeit with different latencies after BMT; C/EBPα-N321D induced AML with the shortest latency. By analyzing the gene expression profiles of C/EBPα-N321D- and mock-transduced c-kit+ Sca-1+ Lin− cells, we identified Csf1r as a gene downregulated by C/EBPα-N321D. In addition, leukemic cells expressing C/EBPα-Cm exhibited low levels of colony stimulating factor 1 receptor in mice. On the other hand, transduction with C/EBPα-Nm did not influence Csf1r expression in c-kit+ Sca-1+ Lin− cells, implying a unique role for C/EBPα-Cm in downregulating Csf1r . Importantly, Csf1r overexpression collaborated with C/EBPα-N321D to induce fulminant AML with leukocytosis in mouse BMT models to a greater extent than did C/EBPα-N321D alone. Collectively, these results suggest that C/EBPα-Cm -mediated downregulation of Csf1r has a negative, rather than a positive, impact on the progression of AML involving C/EBPα-Cm , which might possibly be accelerated by additional genetic and/or epigenetic alterations inducing Csf1r upregulation.