TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells

Hao Wang, R. Alejandro Sica, Gurbakhash Kaur, Phillip M. Galbo, Zhixin Jing, Christopher D. Nishimura, Xiaoxin Ren, Ankit Tanwar, Bijan Etemad-Gilbertson, Britta Will, Deyou Zheng, David Fooksman and Xingxing Zang ()
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Hao Wang: Albert Einstein College of Medicine
R. Alejandro Sica: Albert Einstein College of Medicine
Gurbakhash Kaur: UT Southwestern Medical Center
Phillip M. Galbo: Albert Einstein College of Medicine
Zhixin Jing: Albert Einstein College of Medicine
Christopher D. Nishimura: Albert Einstein College of Medicine
Xiaoxin Ren: Albert Einstein College of Medicine
Ankit Tanwar: Albert Einstein College of Medicine
Bijan Etemad-Gilbertson: NextPoint Therapeutics, Inc
Britta Will: Albert Einstein College of Medicine
Deyou Zheng: Albert Einstein College of Medicine
David Fooksman: Albert Einstein College of Medicine
Xingxing Zang: Albert Einstein College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Acute myeloid leukemia (AML) is initiated and sustained by a hierarchy of leukemia stem cells (LSCs), and elimination of this cell population is required for curative therapies. Here we show that transmembrane and immunoglobulin domain containing 2 (TMIGD2), a recently discovered co-stimulatory immune receptor, is aberrantly expressed by human AML cells, and can be used to identify and enrich functional LSCs. We demonstrate that TMIGD2 is required for the development and maintenance of AML and self-renewal of LSCs but is not essential for normal hematopoiesis. Mechanistically, TMIGD2 promotes proliferation, blocks myeloid differentiation and increases cell-cycle of AML cells via an ERK1/2-p90RSK-CREB signaling axis. Targeting TMIGD2 signaling with anti-TMIGD2 monoclonal antibodies attenuates LSC self-renewal and reduces leukemia burden in AML patient-derived xenograft models but has negligible effect on normal hematopoietic stem/progenitor cells. Thus, our studies reveal the function of TMIGD2 in LSCs and provide a promising therapeutic strategy for AML.

Date: 2024
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DOI: 10.1038/s41467-023-43843-6

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