Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development
Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato
Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato
View: Text | PDF
Research Article Oncology

Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development

Abstract

Cancer cells reprogram lipid metabolism during their malignant progression, but limited information is currently available on the involvement of alterations in fatty acid synthesis in cancer development. We herein demonstrate that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid synthesis, plays a critical role in regulating the growth and differentiation of leukemia-initiating cells. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPA, a transcription factor regulating myeloid differentiation, for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). We identified ACC1 as a target of the Trib1-COP1 complex and found that an ACC1 mutant resistant to degradation because of the lack of a Trib1-binding site attenuated complex-driven leukemogenesis. Stable ACC1 protein expression suppressed the growth-promoting activity and increased ROS levels with the consumption of NADPH in a primary bone marrow culture, and delayed the onset of AML with increases in mature myeloid cells in mouse models. ACC1 promoted the terminal differentiation of Trib1-COP1–expressing cells and eradicated leukemia-initiating cells in the early phase of leukemic progression. These results indicate that ACC1 is a natural inhibitor of AML development. The upregulated expression of the ACC1 protein has potential as an effective strategy for cancer therapy.

Authors

Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato

×

Figure 5

Stabilized ACC1 suppresses leukemic progression and induces cell differentiation in AML.

Options: View larger image (or click on image) Download as PowerPoint
Stabilized ACC1 suppresses leukemic progression and induces cell differe...
Mice were transplanted with BM cells infected with retroviruses expressing Trib1- and COP1-IRES-GFP together with and without K1759R and Helix1mut and analyzed for several months after BM transplantation. (A) Myeloid leukemia–free survival curves of transplanted mice. Results are derived from 4 independent transfer experiments. P values versus Trib1-COP1 control mice were calculated with the log-rank test. (B) May-Grünwald-Giemsa–stained peripheral blood (PB) smears and cytospins of BM cells in AML mice. Original magnification, ×400. (C) Frequency of neutrophils in the PB and BM cells of Trib1/COP1 (n = 10), K1759R (n = 9), and Helix1mut (n = 4) mice. P values were calculated with 1-way ANOVA with Tukey’s multiple-comparison post-test (**P < 0.01, ***P < 0.001). Data are shown as mean ± SEM. (D) FACS analysis of GFP-positive BM cells for immature (Mac-1lo, Gr-1lo) and differentiated (Mac-1hi, Gr-1hi) granulocytes. The population of GFP-positive cells in BM is shown in the top panels. The distribution pattern in normal BM cells is shown in the left panels. (E) A detailed FACS analysis of GFP-positive BM cells for lineage-negative cells, excluding Mac-1 and Gr-1 (Lin*–: CD3–B220–TER-119–). Lin*–Sca-1– (Lin*: lineage marker without Mac-1 and Gr-1) BM cells were separated into 3 fractions: c-KithiMac-1– (fraction A: the CMP/GMP/MEP compartment), c-Kit+Mac-1+ (fraction B: committed myeloid progenitors), and c-Kitlo/–Mac-1+ (fraction C: differentiated myeloid cells). The distribution pattern in normal BM cells is shown in the left panels. (F) Total RNA extracted from GFP-positive BM cells was analyzed by semi-qRT-PCR using a pair of primers specific to hACC1, Trib1, COP1, and β-actin.