Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation.

Sisi Chen Rahul S Vedula Antonio Cuevas-Navarro Bin Lu Simon J Hogg Eric Wang Salima Benbarche Katherine Knorr Won Jun Kim Robert F Stanley Hana Cho Caroline Erickson Michael Singer Dan Cui Steven Tittley Benjamin H Durham Tatiana S Pavletich Elise Fiala Michael F Walsh Daichi Inoue Sebastien Monette Justin Taylor Neal X Rosen Frank McCormick R Coleman Lindsley Hatice Ulku Osmanbeyoglu Omar Abdel-Wahab

Published in: Cancer discovery (2022)

Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia. This article is highlighted in the In This Issue feature, p. 2221.

Keyphrases

wild type
acute myeloid leukemia
bone marrow
cell proliferation
signaling pathway
tyrosine kinase
machine learning
deep learning
antibiotic resistance genes
microbial community
neural network