Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells

Zhang, Siming; Isaji, Tomoya; Zheng, Meng; Wang, Yue; Wu, Tiangui; Saito, Tsukushi; Zhou, Yuhang; Fukuda, Tomohiko; Takahashi, Shinichiro; Gu, Jianguo

doi:10.3390/biom16050756

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Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells

by

Siming Zhang

^1,2,

Tomoya Isaji

^1,3

,

Meng Zheng

¹,

Yue Wang

¹,

Tiangui Wu

¹,

Tsukushi Saito

¹,

Yuhang Zhou

¹,

Tomohiko Fukuda

^1,3,

Shinichiro Takahashi

^3,4,*

and

Jianguo Gu

^1,3,*

¹

Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

²

Department of Cancer Research Center, Nantong Tumor Hospital, The Affiliated Tumor Hospital of Nantong University, Nantong 226006, China

³

Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan

⁴

Division of Laboratory Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai 983-8536, Japan

^*

Authors to whom correspondence should be addressed.

Biomolecules 2026, 16(5), 756; https://doi.org/10.3390/biom16050756 (registering DOI)

Submission received: 16 April 2026 / Revised: 19 May 2026 / Accepted: 19 May 2026 / Published: 21 May 2026

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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Abstract

Glycosylation is essential for hematopoietic cell homeostasis and malignant transformation. Dysregulated expression of glycosylation genes in leukemia cells accelerates disease progression and fosters drug resistance. Therefore, targeting these genes offers a promising avenue for anti-leukemic therapy. In this study, we explore the roles of N-glycans in acute promyelocytic leukemia (APL) differentiation using the ATRA-induced wild-type NB4 (WT/ATRA) or HL-60 cell model. We found that expression of N-acetylglucosaminyltransferase IVa (GnT-IVa, encoded by the MGAT4A gene) and its product (β1,4-GlcNAc-branched N-glycan) increased significantly during differentiation, as evaluated by lectin blot, real-time PCR, and flow cytometry. Interestingly, analysis of the Gene Expression Omnibus (GEO) public data showed that MGAT4A expression is significantly lower in APL patients, and higher MGAT4A expression was associated with favorable survival in AML cohorts. To address the role of GnT-IVa in differentiation, we established MGAT4A- and MGAT4B-knockout (KO) NB4 cell lines using CRISPR/Cas9. Compared to WT/ATRA cells, MGAT4A KO, but not MGAT4B KO, markedly suppressed ATRA-induced differentiation, as evidenced by reduced expression of CD11b and CD11c. We found that CD11b is a major glycoprotein carrying β1,4-GlcNAc-branched N-glycans. This modification enhanced CD11b stability, as CD11b expression declined more rapidly in MGAT4A KO cells in the presence of cycloheximide. In addition, MGAT4A KO suppressed ERK/MAPK signaling, which contributed to differentiation. Our study highlights the critical role of GnT-IVa in regulating APL differentiation, which may provide a basis for developing new differentiation therapies for APL.

Keywords: GnT-IVa; N-glycan; cell differentiation; leukemia cells

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MDPI and ACS Style

Zhang, S.; Isaji, T.; Zheng, M.; Wang, Y.; Wu, T.; Saito, T.; Zhou, Y.; Fukuda, T.; Takahashi, S.; Gu, J. Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells. Biomolecules 2026, 16, 756. https://doi.org/10.3390/biom16050756

AMA Style

Zhang S, Isaji T, Zheng M, Wang Y, Wu T, Saito T, Zhou Y, Fukuda T, Takahashi S, Gu J. Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells. Biomolecules. 2026; 16(5):756. https://doi.org/10.3390/biom16050756

Chicago/Turabian Style

Zhang, Siming, Tomoya Isaji, Meng Zheng, Yue Wang, Tiangui Wu, Tsukushi Saito, Yuhang Zhou, Tomohiko Fukuda, Shinichiro Takahashi, and Jianguo Gu. 2026. "Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells" Biomolecules 16, no. 5: 756. https://doi.org/10.3390/biom16050756

APA Style

Zhang, S., Isaji, T., Zheng, M., Wang, Y., Wu, T., Saito, T., Zhou, Y., Fukuda, T., Takahashi, S., & Gu, J. (2026). Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells. Biomolecules, 16(5), 756. https://doi.org/10.3390/biom16050756

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Upregulation of GnT-IVa and Its Critical Roles in ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells

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