Cooperative loss of RAS feedback regulation drives myeloid leukemognesis

RAS network activation is common in human cancers and, in acute myeloid leukemia (AML), achieved mainly through gain-of-function mutations in KRAS , NRAS , or the FLT3 receptor tyrosine kinase 1 . In mice, we show that premalignant myeloid cells harboring a Kras G12D allele retain low Ras signaling owing to a negative feedback involving Spry4 that prevents transformation. In humans, SPRY4 is located on chromosome 5q, a region affected by large heterozygous deletion that are associated with an aggressive disease in which gain-of-function RAS pathway mutations are rare. These 5q deletions often co-occur with chromosome 17 alterations involving deletion of NF1 - another RAS negative regulator - and TP53 . Accordingly, combined suppression of Spry4, Nf1 and Trp53 produces high Ras signaling and drives AML in mice. Therefore, SPRY4 is a 5q tumor suppressor whose disruption contributes to a lethal AML subtype that appears to acquire RAS pathway activation through loss of negative regulators.