title: 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.
abstract: 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-N(m)) generating p30 as a dominant form and C-terminal basic leucine zipper domain mutants (C/EBPα-C(m)). We have previously shown that C/EBPα-K304_R323dup belonging to C/EBPα-C(m), but not C/EBPα-T60fsX159 belonging to C/EBPα-N(m), alone induced AML in mouse bone marrow transplantation (BMT) models. Here we show that various C/EBPα-C(m) mutations have a similar, but not identical, potential in myeloid leukemogenesis. Notably, like C/EBPα-K304_R323dup, any type of C/EBPα-C(m) 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-C(m) exhibited low levels of colony stimulating factor 1 receptor in mice. On the other hand, transduction with C/EBPα-N(m) did not influence Csf1r expression in c-kit(+)Sca-1(+)Lin(-) cells, implying a unique role for C/EBPα-C(m) 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-C(m)-mediated downregulation of Csf1r has a negative, rather than a positive, impact on the progression of AML involving C/EBPα-C(m), which might possibly be accelerated by additional genetic and/or epigenetic alterations inducing Csf1r upregulation.
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Togami
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Inoue
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Koutarou
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kimihito C
authors.initials: KC
authors.lastname: Kawabata
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Nagase
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Horikawa
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Izawa
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomofusa
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakahara
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan; Division of Radiation Information Registry, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan; Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: kitamura@ims.u-tokyo.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers; D016186:Receptor, Macrophage Colony-Stimulating Factor