Abstract
Mutations that activate RAS proto-oncogenes and their effectors are common in acute myeloid leukemia (AML); however, efforts to therapeutically target Ras or its effectors have been unsuccessful, and have been hampered by an incomplete understanding of which effectors are required for AML proliferation and survival. We investigated the role of Ras effector pathways in AML using murine and human AML models. Whereas genetic disruption of NRAS(V12) expression in an NRAS(V12) and Mll-AF9-driven murine AML induced apoptosis of leukemic cells, inhibition of phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) signaling did not reproduce this effect. Conversely, genetic disruption of RALB signaling induced AML cell death and phenocopied the effects of suppressing oncogenic Ras directly – uncovering a novel role for RALB signaling in AML survival. Knockdown of RALB led to decreased phosphorylation of TBK1 and reduced BCL2 expression, providing mechanistic insight into RALB survival signaling in AML. Notably, we found that patient-derived AML blasts have higher levels of RALB-TBK1 signaling compared to normal blood leukocytes, supporting a pathophysiologic role for RALB signaling for AML patients. Overall, our work provides new insight into the specific roles of Ras effector pathways in AML and has identified RALB signaling as a key survival pathway.
Highlights
The NRAS and KRAS proto-oncogenes and genes that regulate Ras activation (i.e. PTPN11 and NF1) are frequently mutated in acute myeloid leukemia (AML)
TNM AML cells conditionally express the NRAS(V12) oncogene from a tetracycline-response element (TRE) promoter, and NRAS(V12) transcription can be suppressed by administering the tetracycline analog doxycycline (Dox)
The effects of genetic disruption of NRAS(V12) in the tNM AML model supports a critical role of Ras signaling to support AML survival
Summary
The NRAS and KRAS proto-oncogenes and genes that regulate Ras activation (i.e. PTPN11 and NF1) are frequently mutated in AML. Many common mutations in AML occur upstream of Ras (i.e. FLT3 ITD and KIT), and likely rely on Ras signaling for their oncogenic effects [1,2,3]. There is a limited understanding of how specific Ras effector pathways maintain AML proliferation and survival. Ras proteins act as molecular switches to modulate signal transduction by cycling between active guanine triphosphate (GTP)-bound and inactive guanine diphosphate (GDP)-bound states [7]. Oncogenic mutations in RAS genes, most commonly involving amino acid substitutions at codons 12, 13, and 61 impair GTP hydrolysis, thereby leading to constitutive activation www.impactjournals.com/oncotarget of Ras effector pathways and cellular transformation [9]. Ras-GTP regulates cell proliferation and survival by interacting with a variety of effector enzymes
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