Activation of NOTCH signaling impedes cell proliferation and survival in acute megakaryoblastic leukemia.
Kelly Ooi Kee OngMichelle Meng Huang MokAkiko Niibori-NambuLinsen DuMasatoshi YanagidaChelsia Qiuxia WangAvinash Govind BahirvaniDesmond Wai Loon ChinCai Ping KohKing Pan NgNamiko YamashitaBindya JacobTomomasa YokomizoHitoshi TakizawaTakayoshi MatsumuraToshio SudaJie-Ying Amelia LauTuan Zea TanSeiichi MoriHenry YangMasayuki IwasakiTakashi MinamiNorio AsouQiao-Yang SunLing-Wen DingH Phillip KoefflerDaniel G TenenRitsuko ShimizuMasayuki YamamotoYoshiaki ItoShirley Kow Yin KhamAllen Eng-Juh YeohWee Joo ChngMotomi OsatoPublished in: Experimental hematology (2024)
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.