Identification of a Wnt-specific Activator Sheds New Light on Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell (HSC) Transplantation is now a popular therapeutic strategy for patients with cancers of the blood or bone marrow, such as multiple myeloma or leukemia. However, HSC expansion remains a big concern and challenge facing this field. Wnt/β-catenin signaling plays an important role in HSC formation and self-renewal, and is essential for HSC recovery after injury and in transplantation.

A research group led by Prof. LI Lin in Shanghai Institute of Biochemistry and Cell Biology identified a novel Wnt activator HLY78, 4-ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine, as a potential HSC expansion inducer. They showed that HLY78 activates Wnt/β-catenin signaling pathway in a Wnt ligand-dependent manner. They further revealed the working mechanism that HLY78 directly targets the DAX domain of Axin to relieve its autoinhibition, thus promoting Axin–LRP6 complex formation and consequently Wnt signaling transduction. Importantly, HLY78 increases the expression of the conserved HSC markers, runx1 and cmyb, in zebrafish embryos, further supporting the role of HLY78 in regulating HSC development.

These findings not only lead to the identification of a new drug candidate in facilitating HSC expansion, but also provide important novel mechanistic insights into the role of Axin in Wnt/β-catenin signaling.

This research entitled “Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction” was published in Nature Chemical Biology on July 28, 2013.

This work was done in collaboration with Prof. HAO Xiaojiang in Kunming Institute of Botany, and helped by Prof. ZENG Rong in Shanghai Institute of Biochemistry and Cell Biology and Prof. PAN Weijun in Shanghai Institute of Health Sciences. This work is supported by the Ministry of Science and Technology of China and the National Natural Science Foundation of China.

A small-molecule activator of Wnt/β-catenin signaling acts by binding a negative regulator of β-catenin, Axin, leading to a conformational change that promotes association of Axin with LRP6. (Image by Prof. LI Lin)