Simultaneous Deletion of RAS Negative Feedback Genes Promotes AML

Acute myelogenous leukemia (AML) is often characterized by gain-of-function mutations and copy-number amplification of RAS pathway genes that increase downstream MAPK and PI3K signaling to drive oncogenic transformation. Previous studies have shown that oncogenic Kras^G12D synergizes with Trp53 loss to promote AML development in mouse models. However, consistent with previous studies, Zhao and colleagues found that expression of Kras^G12D alone was not sufficient to induce sustained activation of MAPK and PI3K in premalignant myeloid cells, suggesting that compensatory negative feedback mechanisms may limit RAS-mediated leukemogenesis. In support of this idea, expression of the RAS negative feedback gene Sprouty 4 (Spry4) was increased in myeloid cells expressing mutant Kras^G12D, and depletion of Spry4 in Kras^G12D-expressing hematopoietic stem and progenitor cells (HSPC) resulted in elevated RAS signaling and accelerated leukemogenesis in mice. Furthermore, SPRY4 deletion was frequently detected in human AML samples harboring deletion of chromosome 5q [del(5q)] that lack gain-of-function RAS mutations, and often occurred in combination with loss of TP53 and other RAS negative feedback genes, including neurofibromin 1 (NF1), suggesting that deletion of multiple negative regulators may facilitate RAS activation in del(5q) AML in the absence of activating mutations. Indeed, concomitant suppression of Spry4 and Nf1 in Trp53-null HSPCs significantly increased the activation of MAPK and PI3K signaling and enhanced the development of myeloid leukemia in transplanted mice, resulting in leukemic cell dissemination and decreased overall survival. These results identify SPRY4 as a tumor suppressor gene in del(5q) AML and support the idea that simultaneous deletion of negative feedback regulators may represent a broad mechanism to drive high levels of RAS signaling in various tumor types.

Zhao Z, Chen CC, Rillahan CD, Shen R, Kitzing T, McNerney ME, et al. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet 2015 Mar 30 [Epub ahead of print].