Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: Lessons from clinical data and BMT models

Naoko Kato, Jiro Kitaura, Noriko Doki, Yukiko Komeno, Naoko Watanabe-Okochi, Katsuhiro Togami, Fumio Nakahara, Toshihiko Oki, Yutaka Enomoto, Yumi Fukuchi, Hideaki Nakajima, Yuka Harada, Hironori Harada, Toshio Kitamura

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45 Citations (Scopus)

Abstract

Two types of mutations of a transcription factor CCAAT-enhancer binding protein α (C/EBPα) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBPα-Nm)-transduced cells, a C-terminal mutant (C/EBPα-Cm)-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBPα-Cm collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBPα-Cm strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBPα-Cm failed to inhibit transcriptional activity of wild-type C/EBPα, it suppressed the synergistic effect between C/EBPα and PU.1. On the other hand, C/EBPα-Nm inhibited C/EBPα activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBPα-Nm. Thus, 2 types of C/EBPα mutations are implicated in leukemogenesis, involving different and cooperating molecular mechanisms.

Original languageEnglish
Pages (from-to)221-233
Number of pages13
JournalBlood
Volume117
Issue number1
DOIs
Publication statusPublished - 2011 Jan 6

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kato, N., Kitaura, J., Doki, N., Komeno, Y., Watanabe-Okochi, N., Togami, K., Nakahara, F., Oki, T., Enomoto, Y., Fukuchi, Y., Nakajima, H., Harada, Y., Harada, H., & Kitamura, T. (2011). Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: Lessons from clinical data and BMT models. Blood, 117(1), 221-233. https://doi.org/10.1182/blood-2010-02-270181