Activation of NOTCH signaling impedes cell proliferation and survival in acute megakaryoblastic leukemia

• Published in: Experimental hematology Vol. 137; p. 104255
• Main Authors: Ong, Kelly Ooi Kee, Mok, Michelle Meng Huang, Niibori-Nambu, Akiko, Du, Linsen, Yanagida, Masatoshi, Wang, Chelsia Qiuxia, Bahirvani, Avinash Govind, Chin, Desmond Wai Loon, Koh, Cai Ping, Ng, King Pan, Yamashita, Namiko, Jacob, Bindya, Yokomizo, Tomomasa, Takizawa, Hitoshi, Matsumura, Takayoshi, Suda, Toshio, Lau, Jie-ying Amelia, Tan, Tuan Zea, Mori, Seiichi, Yang, Henry, Iwasaki, Masayuki, Minami, Takashi, Asou, Norio, Sun, Qiao-Yang, Ding, Ling-Wen, Koeffler, H. Phillip, Tenen, Daniel G., Shimizu, Ritsuko, Yamamoto, Masayuki, Ito, Yoshiaki, Kham, Shirley Kow Yin, Yeoh, Allen Eng-Juh, Chng, Wee Joo, Osato, Motomi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.09.2024
• Subjects: GATA-1; Down syndrome; Notch; RUNX1
• ISSN: 0301-472X; 1873-2399; 1873-2399
• DOI: 10.1016/j.exphem.2024.104255

•NOTCH pathway genes are frequently mutated in acute megakaryoblastic leukemia (AMKL).•Pharmacological NOTCH activation suppresses AMKL cell proliferation.•Baits in targeted sequencing should be carefully designed for NOTCH pathway genes. The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines and detected frequent genetic mutations in the NOTCH pathway in addition to previously reported alterations in GATA-1 and the JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient-derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis. and NOTCH activation holds the potential for therapeutic application in AMKL.