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ACUTE MYELOID LEUKEMIA

Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation

Abstract

The identification of characteristic differences between cancer stem cells and their normal counterparts remains a key challenge for cancer treatment. Here, we investigated the role of immunoglobulin superfamily member 8 (Igsf8, also known as EWI-2, PGRL, and CD316) on normal and malignant hematopoietic stem cells, mainly using the conditional knockout model. Deletion of Igsf8 did not affect steady state hematopoiesis, but it led to a significant improvement of survival in mouse myeloid leukemia models. Deletion of Igsf8 significantly depletes leukemia stem cells (LSCs) through enhanced apoptosis and β-catenin degradation. At a molecular level, we found that activation of β-catenin in LSCs depends on Igsf8, which promotes the association of FZD4 with its co-receptor LRP6 in the presence of Igsf8. Similarly, IGSF8 inhibition blocks the colony-forming ability of LSCs and improves the survival of recipients in xenograft models of myeloid leukemia. Collectively, these data indicate strong genetic evidence identifying Igsf8 as a key regulator of myeloid leukemia and the possibility that targeting IGSF8 may serve as a new therapeutic approach against myeloid leukemia.

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Fig. 1: Igsf8 is dispensable in steady-state hematopoiesis.
Fig. 2: Igsf8 deletion impairs initiation and propagation of myeloid leukemia.
Fig. 3: Igsf8 deletion depletes leukemia stem cells and leads to increased apoptosis.
Fig. 4: IGSF8 is required for human myeloid leukemia.
Fig. 5: Igsf8 deletion downregulates the β-catenin pathway in myeloid leukemia.
Fig. 6: Igsf8 deletion led to an increase of phosphorylated β-catenin through impaired FZD4-LRP6 receptor interaction in myeloid leukemia.

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Acknowledgements

We thank the lab members in Division of Molecular Therapy and FACS Core Laboratory (The Institute of Medical Science, The University of Tokyo) for helpful support and comments. We would like to thank Naokazu Inoue (Fukushima Medical University) for the Igsf8flox/flox mice line, Toshio Kitamura (The Institute of Medical Science, The University of Tokyo) for the pMYs-IRES-GFP vector, and Susumu Goyama (University of Tokyo) for the human β-CATENIN construct. Igsf8flox/flox mice (strain: B6D2;129S2-Igsf8 < tm1.1Osb > ; RBRC05637) were provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan. This research was funded by the SGH foundation, the Japanese Society of Hematology Research Grant, the Princess Takamatsu Cancer Research Fund, and the Cooperative Research Program (Joint Usage/Research Center program) of Institute for Frontier Life and Medical Sciences, Kyoto University. This research was also supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (20K08748 to TK; 20J10521 to KJ; 19H05746 to AI). KJ is also supported by a doctoral course fellowship from the JSPS.

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KJ performed the majority of experiments, analyzed the data, and contributed to the writing the paper. YNT performed the RNA sequencing analysis. SK supported the data of immunofluorescence staining. YN, and AI wrote and edited the manuscript. TK planned and guided the research, and wrote the paper. All authors approved the final version.

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Correspondence to Takaaki Konuma.

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Jimbo, K., Nakajima-Takagi, Y., Ito, T. et al. Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation. Leukemia 36, 1550–1562 (2022). https://doi.org/10.1038/s41375-022-01564-7

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