Novel Insights into the Role of Kras in Myeloid Differentiation: Engaging with Wnt/β-Catenin Signaling

Noriko Yokoyama; Hitoshi Nakayama; Kazuhisa Iwabuchi

doi:10.3390/cells12020322

Novel Insights into the Role of Kras in Myeloid Differentiation: Engaging with Wnt/β-Catenin Signaling

Cells. 2023 Jan 14;12(2):322. doi: 10.3390/cells12020322.

Authors

Noriko Yokoyama¹, Hitoshi Nakayama^{1

2

3}, Kazuhisa Iwabuchi^{1

2

3}

Affiliations

¹ Institute for Environmental and Gender Specific Medicine, Graduate School of Medicine, Juntendo University, Urayasu 279-0021, Chiba, Japan.
² Infection Control Nursing, Graduate School of Health Care and Nursing, Juntendo University, Urayasu 279-0012, Chiba, Japan.
³ Laboratory of Biochemistry, Faculty of Health Care and Nursing, Juntendo University, Urayasu 279-0023, Chiba, Japan.

Abstract

Cells of the HL-60 myeloid leukemia cell line can be differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The molecular mechanisms involved in this differentiation process, however, remain unclear. This review focuses on the differentiation of HL-60 cells. Although the Ras proteins, a group of small GTP-binding proteins, are ubiquitously expressed and highly homologous, each has specific molecular functions. Kras was shown to be essential for normal mouse development, whereas Hras and Nras are not. Kras knockout mice develop profound hematopoietic defects, indicating that Kras is required for hematopoiesis in adults. The Wnt/β-catenin signaling pathway plays a crucial role in regulating the homeostasis of hematopoietic cells. The protein β-catenin is a key player in the Wnt/β-catenin signaling pathway. A great deal of evidence shows that the Wnt/β-catenin signaling pathway is deregulated in malignant tumors, including hematological malignancies. Wild-type Kras acts as a tumor suppressor during DMSO-induced differentiation of HL-60 cells. Upon DMSO treatment, Kras translocates to the plasma membrane, and its activity is enhanced. Inhibition of Kras attenuates CD11b expression. DMSO also elevates levels of GSK3β phosphorylation, resulting in the release of unphosphorylated β-catenin from the β-catenin destruction complex and its accumulation in the cytoplasm. The accumulated β-catenin subsequently translocates into the nucleus. Inhibition of Kras attenuates Lef/Tcf-sensitive transcription activity. Thus, upon treatment of HL-60 cells with DMSO, wild-type Kras reacts with the Wnt/β-catenin pathway, thereby regulating the granulocytic differentiation of HL-60 cells. Wild-type Kras and the Wnt/β-catenin signaling pathway are activated sequentially, increasing the levels of expression of C/EBPα, C/EBPε, and granulocyte colony-stimulating factor (G-CSF) receptor.

Keywords: HL-60 cells differentiation; Wnt/β-catenin; acute myeloid leukemia; hematopoietic stem cells; tumor suppressor; wild-type Kras.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Dimethyl Sulfoxide / pharmacology
Hematopoiesis
Mice
Wnt Proteins / metabolism
Wnt Signaling Pathway*
beta Catenin* / metabolism

Substances

beta Catenin
Dimethyl Sulfoxide
Wnt Proteins

Grants and funding

This study was supported in part by grants from the Foundation of Strategic Research Projects in Private Universities (S1311011), AMED under Grant Number 21gm0910006h0106, and Collaborative Incentive Research Grant from Juntendo University Faculty of Healthcare and Nursing (to K.I.), and MEXT KAKENHI grant number 18H00451 (to N.Y).