【Publications】Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia

July 16 2024

Labs: Motomi Osato, Hitoshi Takizawa, Goro Sashida, Toshio Suda

Paper information

Title:

Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia

Akiko Niibori-Nambu, Chelsia Qiuxia Wang, Desmond Wai Loon Chin, Jing Yuan Chooi, Hiroki Hosoi, Takashi Sonoki, Cheng-Yong Tham, Giselle Sek Suan Nah, Branko Cirovic, Darren Qiancheng Tan, Hitoshi Takizawa, Goro Sashida, Goh Yufen, Tng Jiaqi, Fam Wee Nih, Melissa Jane Fullwood, Toshio Suda, Henry Yang, Vinay Tergaonkar, Ichiro Taniuchi, Shang Li, Wee Joo Chng and Motomi Osato

Gene. 2024 Jul 11:148761. doi: 10.1016/j.gene.2024.148761.

URL: https://www.sciencedirect.com/science/article/abs/pii/S0378111924006425?via%3Dihub

Highlights

• ITGA9 is a leukemic stem cell marker in AML.
• The osteopontin-ITGA9 balance plays a role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status.

Abstract:

Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with soluble osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.

Graphical abstract