Details

Autor(en) / Beteiligte

• Lee, Dong-hee
• Kang, Seong-Ho
• Choi, Da-som
• Ko, Minkyung
• Choi, Eunji
• Ahn, Hyejin
• Min, Hophil
• Oh, Soo Jin
• Lee, Myeong Sup
• Park, Yoon
• Jin, Hyung-seung

Titel

Genome wide CRISPR screening reveals a role for sialylation in the tumorigenesis and chemoresistance of acute myeloid leukemia cells

Ist Teil von

• Cancer letters, 2021-07, Vol.510, p.37-47

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• Aberrant activation of cytokine and growth factor signal transduction pathways confers enhanced survival and proliferation properties to acute myeloid leukemia (AML) cells. However, the mechanisms underlying the deregulation of signaling pathways in leukemia cells are unclear. To identify genes capable of independently supporting cytokine-independent growth, we employed a genome-wide CRISPR/Cas9-mediated loss-of-function screen in GM-CSF-dependent human AML TF-1 cells. More than 182 genes (p < 0.01) were found to suppress the cytokine-independent growth of TF-1 cells. Among the top hits, genes encoding key factors involved in sialylation biosynthesis were identified; these included CMAS, SLC35A1, NANS, and GNE. Knockout of either CMAS or SLC35A1 enabled cytokine-independent proliferation and survival of AML cells. Furthermore, NSG (NOD/SCID/IL2Rγ-/-) mice injected with CMAS or SLC35A1-knockout TF-1 cells exhibited a shorter survival than mice injected with wild-type cells. Mechanistically, abrogation of sialylation biosynthesis in TF-1 cells induced a strong activation of ERK signaling, which sensitized cells to MEK inhibitors but conferred resistance to JAK inhibitors. Further, the surface level of α2,3-linked sialic acids was negatively correlated with the sensitivity of AML cell lines to MEK/ERK inhibitors. We also found that sialylation modulated the expression and stability of the CSF2 receptor. Together, these results demonstrate a novel role of sialylation in regulating oncogenic transformation and drug resistance development in leukemia. We propose that altered sialylation could serve as a biomarker for targeted anti-leukemic therapy. •Abrogation of sialylation promotes the GM-CSF independent proliferation and tumorigenesis of AML cells.•Desialylation modulates the expression and stability of the GM-CSF receptor.•Disruption of sialylation induces resistance to JAK inhibitors and sensitivity to MEK inhibitors.•The surface α2,3-linked sialic acids is negatively correlated with the sensitivity of AML cells to MEK/ERK inhibitors.